Bortezomib plus dexamethasone is highly effective inrelapsed and refractory myeloma patients but responses areshort-livedAlessandro Corso, Marzia Varettoni, Silvia Mangiacavalli, Patrizia Zappasodi, Gian Matteo Pica,Alessandra Algarotti, Cristiana Pascutto, Mario Lazzarino

Division of Hematology, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy

Despite recent advances in therapy, multiple myeloma

(MM) patients eventually relapse and become refractory

to treatment with a median survival ranging from 6 to

9 months (1–3). In the last years, the clinical course of

MM has changed after the introduction of new agents

which interfere with malignant plasma cells and bone

marrow microenvironment. Bortezomib, the former of a

new class of agents known as proteasome inhibitors, has

proven to be very effective in treating relapsed ⁄ refractorymyeloma patients. Two phase II (4, 5) studies have

reported a response rate ranging between 35% and 50%

with a median duration of response (DOR) of

13.7 months. In the APEX study, an international multi-

center randomized trial comparing bortezomib with

high-dose dexamethasone, bortezomib was superior to

high-dose dexamethasone in terms of response rate, time

to progression (TTP) and overall survival (OS) overcom-

ing all the known negative prognostic factors (6). These

results have been successively confirmed in an updated

extended follow-up of APEX study in which bortezomib

demonstrated in relapsed ⁄ refractory MM to give a sur-

vival advantage with respect to conventional therapy

despite substantial crossover of patients from dexametha-

sone to bortezomib (7). The most common adverse

Abstract

Objectives: Bortezomib has proven to be effective as single agent in myeloma patients. Aim of this study

was to evaluate the efficacy and toxicity of bortezomib in combination with dexamethasone in a cohort of

multiple myeloma (MM) relapsed ⁄ refractory patients treated in a single center. Patients and Methods: In

this single center study, 70 patients were treated with bortezomib alone (9) or in combination with dexa-

methasone (61). Results: Forty-one patients (59%) achieved at least a partial response (PR), including 7%

complete response (CR), 36% very good partial response (VGPR) reaching the best response within four

cycles. The duration of response was significantly longer for patients achieving CR ⁄ VGPR than for those

achieving PR (7.3 vs. 3.8 months, P = 0.03). Likewise, time to progression, time to alternative treatment,

and treatment free interval were significantly better for patients obtaining CR ⁄ VGPR (6.8, 9.4, 6.5 months

respectively) as compared with PR (4.9, 6.3, 2 months respectively). The only dose-limiting toxicity was

peripheral neuropathy (PN), which occurred in 38 ⁄ 70 patients (55%) and was of grade 3–4 in 12 (17%). PN

led to a dose reduction or treatment discontinuation in 17 (24%) patients. Complete resolution or improve-

ment of PN occurred in 29 ⁄ 38 (76%) after a median time of 100 d (range: 17–202). Conclusions: Bortezo-

mib in combination with dexamethasone is highly effective in relapsed ⁄ refractory MM producing an

impressive rate of CR ⁄ VGPR, but responses are short-lived.

Key words bortezomib; dexamethasone; relapsed ⁄ refractory myeloma; neuropathy

Correspondence Dr Alessandro Corso, Division of Hematology, Foundation IRCCS Policlinico San Matteo, Via Golgi 19, 27100 Pavia,

Italy. Tel: +39 0382 503595; Fax: +39 0382 502250; e-mail: a.corso@smatteo.pv.it

Accepted for publication 9 June 2009 doi:10.1111/j.1600-0609.2009.01295.x

ORIGINAL ARTICLE

European Journal of Haematology 83 (449–454)

ª 2009 John Wiley & Sons A/S 449

events (gastrointestinal symptoms, thrombocytopenia,

and peripheral neuropathy) were always predictable and

manageable.

Few data are available on the use of bortezomib out-

side the context of clinical trials and in particular in

combination with dexamethasone. Aim of this study was

to evaluate the efficacy and toxicity of bortezomib in

combination with dexamethasone in a cohort of MM

relapsed ⁄ refractory patients treated in a single centre.

Patients and methods

We retrospectively evaluated 70 patients with relapsed,

refractory MM treated with bortezomib at the dose of

1.3 mg ⁄m2 on days 1, 4, 8, 11 every 3 wk up to 6–8

cycles alone or in association with dexamethasone at the

dose of 20 mg on the day of bortezomib administration

and on the day thereafter. Efficacy evaluations were per-

formed on the first day of each cycle. Responses were

assessed according to the International Myeloma Work-

ing Group (IMWG) criteria (8). Briefly, a complete

response (CR) was defined by a negative immunofixation

on serum and urine, <5% plasma cells in bone marrow,

and disappearance of any soft-tissue plasmacytoma, if

present at baseline; a very good partial response (VGPR)

was defined as a reduction of 90% or greater of serum

M-protein plus urine M-protein level <100 mg ⁄ 24 h; a

partial response (PR) was defined as a ‡50% reduction

of serum M-protein and reduction of 24-h M-protein by

‡90% or to <200 mg, and a ‡50% reduction in size of

soft-tissue plasmacytomas. Patients not meeting criteria

for CR, VGPR, PR or progressive disease (PD) were

defined as having stable disease (SD). PD was diagnosed

in presence of at least one of the following conditions:

increase of ‡25% from baseline in serum or urine M-pro-

tein (with an absolute increase of at least 0.5 g ⁄dL and

200 mg ⁄ 24 h respectively); increase of ‡25% in bone

marrow plasma cell percentage; development of new

bone lesions or soft-tissue plasmacytomas (or definite

increase in size of pre-existing bone lesions ⁄plasmacyto-

mas); development of hypercalcemia (>11.5 mg ⁄dL).The following baseline factors were evaluated as possible

predictors of response: age, sex, myeloma isotype,

number of previous therapies, previous treatment with

thalidomide, previous high-dose therapy, serum and

urine M-protein levels, serum free-light chains (sFLC)

levels, percentage of bone marrow plasma-cells and pres-

ence of extramedullary disease. The potential role of

sFLC as early predictors of response was evaluated by

comparing changes either in the ratio or in the difference

between involved and uninvolved sFLC from baseline to

cycle 2 day 1. Safety was assessed and graded according

to the National Cancer Institute Common Toxicity Crite-

ria (NCI-CTC) version 3. In patients, who developed a

bortezomib-related peripheral neuropathy (PN), the dose

modifications recommended on the base of experience of

phase II trials were used (9). In detail, in presence of

grade 1 with pain or grade 2 PN the dose was reduced

to 1 mg ⁄m2; in patients with grade 2 with pain or grade

3 PN, bortezomib was withheld until resolution of symp-

toms and then restarted at the dose of 0.7 mg ⁄m2 once a

week; in patients with grade 4 PN bortezomib was per-

manently discontinued. All patients who developed a PN

were treated with gabapentin or pregabalin and with

analgesics. The following variables were evaluated for

their possible correlation with PN: age, sex, number of

prior therapies, prior exposure and duration of therapy

with thalidomide, prior high-dose therapy, presence of

symptomatic neuropathy at baseline.

Statistical analysis

Numeric variables were summarized by their median and

range. Categorical variables were described by counts

and relative frequencies. Association between response to

treatment and categorical baseline factors was tested

using either the two-tailed Fisher exact test (for 2 · 2

tables) or the v2 test (for larger tables). The same test

was applied to investigate the categorical risk factors for

PN. The effect of continuous factors on either response

or PN was tested again using a non-parametric

approach, namely either the Mann–Whitney test or the

Kruskal–Wallis anova. The Kaplan–Meier product-limit

method was used to estimate survival curves, and the

Gehan–Wilcoxon test was adopted to carry out compari-

sons between different groups of patients. The time to

response (TTR) was defined as the time from the first

administration of bortezomib to the first evidence of a

response ‡PR. DOR was assessed only for patients

achieving at least a PR, and was calculated from the date

of the first response to the date of progression. The TTP

was calculated for all patients from the first dose of bort-

ezomib to the date of progression. The time to alterna-

tive treatment (TTAT) and the treatment free interval

(TFI) were calculated respectively from the first and

from the last administration of bortezomib to the start

of a subsequent therapy. Progression-free survival (PFS)

was calculated as the time between the first dose of bort-

ezomib and the date of disease progression or death, or

last follow-up for censored cases. OS was calculated as

the time between the start of treatment and the date of

death or last follow-up for censored cases.

Results

The main characteristics of the 70 patients are summa-

rized in Table 1. Over a median time of 26 months

(range: 2–137) patients had received a median of one

Bortezomib in relapsed myeloma Corso et al.

450 ª 2009 John Wiley & Sons A/S

prior line of therapy (range 1–6): 41 patients (59%) one

prior therapy, 25 (36%) 2–3 prior therapies and 4 (5%)

‡four previous therapies. Prior regimens included high-

dose therapy in 43 patients (61%), and thalidomide in 40

(70%). At the time of analysis, all patients were evalu-

able for response and toxicity. A median number of four

cycles of bortezomib (range: 1–8) were delivered. Bort-

ezomib was planned alone in 12 patients (17%), and in

combination with dexamethasone in 58 (83%) patients.

Three out of 12 patients added dexamethasone during

treatment for a suboptimal response to bortezomib.

Forty-one patients (59%) achieved at least a PR, includ-

ing five (7%) who obtained a CR and 25 (36%) VGPR,

and 11 a PR (16%). Nineteen patients (27%) had SD

and 10 (14%) progressed under treatment. The overall

response rate (ORR) was respectively 61% in patients

receiving bortezomib as second line therapy and 55% in

patients treated in a more advanced phase (P = 0.8).

Nineteen patients (27%) presented at starting therapy an

extramedullary disease. Of these patients 7 ⁄ 19 (37%)

obtained a good response (three PR, three VGPR, one CR).

The median TTR of all cohort was 21 d (range 15–

118). Thirty-nine out of 41 responding patients (95%)

obtained their best response within four cycles, so only

two patients improved their response after four cycle, the

median DOR was 6.1 months (range: 1.5–26.4), and was

significantly longer in patients achieving a CR ⁄VGPR

with respect to those achieving only a PR (7.3 vs.

3.8 months, P = 0.03). With a median follow-up of

10.8 months (range: 0.4–46.7), 58 out of 70 patients

(83%) progressed and 41 (70%) died. PFS was correlated

to the quality of response (Fig. 1). One-yr PFS was 16%.

Median TTP, TTAT and TFI for the entire population

were 5.6 months (range: 0.3–36), 5.8 months (range:

1.4–37.7) and 2.8 months (range: 0.1–32.6) respectively.

TTP, TTAT and TFI varied also in relation to quality of

response (Table 2). Median OS was 14.6 months and 1-

yr survival rate 60%.

None of the baseline parameters affected response. Data

on sFLC at baseline and at day 1 of cycle 2 were available

for 43 patients. A decrease of 50% or greater of the ratio

between involved and uninvolved sFLC after the first cycle

of therapy was associated with a significantly higher prob-

ability to achieve CR or VGPR (P = 0.04).

The most common toxicities were PN, gastrointestinal

symptoms, thrombocytopenia and fatigue. Side-effects

were usually mild (grade 1–2), well tolerated and not

requiring any treatment modification. The main clinically

relevant toxicity was represented by PN, which occurred

in 38 ⁄ 70 patients (55%) after a median time of 67 d from

the first bortezomib administration (range: 13–158).

Grade 1–2 PN was observed in 27 cases (38%) and grade

3–4 in 12 (17%). Five out of 38 patients (13%) with

bortezomib-related PN presented grade 1 PN at baseline.

In 17 patients (24%) dose reduction or treatment discon-

tinuation was performed for PN. At the time of this

Figure 1 Progression-free survival (PFS) according to the quality of

response to Bortezomib. Patients with CR/VGPR have a significantly

longer PFS with respect to other patients. The achievement of a partial

response does not guarantee a better outcome with respect to SD ⁄ PD.

Table 1 Baseline demographic and disease characteristics of patients

Characteristics

No of patients 70

Male ⁄ female 38 ⁄ 32

Median age, years (range) 60 (38–69)

Type of myeloma, number of patients (%)

IgG 36 (51)

IgA 18 (26)

Light chain 15 (21)

IgD 1 (1)

Median number of prior therapies (range) 1 (1–6)

1 [number of patients (%)] 41 (58)

2–3 [number of patients (%)] 25 (36)

‡4 [number of patients (%)] 4 (6)

Prior high-dose therapy

[number of patients (%)]

43 (61)

Prior thalidomide [number of patients (%)] 40 (70)

Median duration of prior therapy

with thalidomide, months (range)

4 (1–93)

Table 2 Outcome according to the quality of response to Bortezomib

Allpatients

CR +VGPR PR

SD +PD P

Number of patients 70 30 11 19

Median TTP, months 5.6 6.8 4.9 – <0.001

Median DOR, months 6.1 7.3 3.8 – 0.03

Median TTAT, months 5.8 9.4 6.3 3.1 0.002

Median TFI, months 2.8 6.5 2 0.7 0.001

Median PFS, months 5.4 8.8 4.7 2.3 <0.0001

TTP: time to progression; DOR: duration of response; TTAT: time to

alternative treatment; TFI: treatment free interval; PFS: progression-

free survival; PR, partial response; VGPR, very good partial response;

CR, complete response.

Corso et al. Bortezomib in relapsed myeloma

ª 2009 John Wiley & Sons A/S 451

analysis, 27 ⁄ 38 patients (71%) showed a complete resolu-

tion of PN and two (5%) a significant improvement of

symptoms. The median time to resolution or improve-

ment of symptoms was 100 (17–276) d. In all patients

with a grade 3–4 neuropathy pain disappeared after a

median time of 99 (17–202) d. The overall incidence of

PN was not influenced by the number of previous regi-

mens, prior use and duration of therapy with thalido-

mide or presence of PN at baseline. On the contrary, the

incidence of grade 3–4 PN increased with age, although

the association did not reach a statistical significance

(P = 0.08). Gastrointestinal symptoms were reported by

22 ⁄ 70 patients (31%), and were of mild severity in the

majority of cases. Only three patients (4%) required

dose reduction or treatment discontinuation for gastro-

intestinal toxicity, Thrombocytopenia was the most

frequent grade 3–4 toxicity (24 ⁄ 70, 35%), but was never

associated with bleeding complications. Because of the

spontaneous recovery of thrombocytopenia during the

10-d rest period between cycles, dose reduction or treat-

ment discontinuation were not required. Other side-

effects less frequently observed were fatigue (eight cases,

11%), herpes-zoster (seven cases, 10%), skin rash (five

cases, 7%), vasculitis (one case) and acute distress respi-

ratory syndrome (one case).

Discussion

The activity and safety of Bortezomib in relapsed, refrac-

tory MM has been clearly demonstrated in several large

multicenter studies (4–7). These studies were mainly per-

formed on Bortezomib used as single agent.

In this study, an objective response was observed in

41 ⁄ 70 evaluable patients (59%), including a substantial

proportion of major responses (CR + VGPR 30 ⁄ 41,73%). These results are consistent with those reported on

624 relapsed and ⁄or refractory MM patients enrolled in

an international phase IIIb study for expanded access to

bortezomib. In that trial 54% of evaluable patients

obtained at least a PR, and 65% of responding patients

obtained a CR or VGPR (10). On the other hand, in the

phase II trials SUMMIT and CREST the overall

response rate was neatly lower (‡PR 27–38%) (4; 5), but

59% of patients enrolled in these studies were treated

with bortezomib alone (11), whereas in our study, 87%

of patients received bortezomib in combination with

dexamethasone. Furthermore, in SUMMIT patients had

been previously treated with a median of six lines of

therapy. The final analysis of APEX study showed that

patients receiving bortezomib earlier have higher

response rates and longer survival (7). Thus, the higher

response rate observed in our study could also be

explained by the high proportion of patients treated in

first relapse (58%) although in our analysis, no difference

in terms of outcome was observed between patients

receiving bortezomib as second line therapy (ORR 61%)

or any other subsequent line of therapy (55%, P = 0.8).

Response to bortezomib was achieved very rapidly, after

a median time of 21 d, namely the first cycle of treat-

ment. There are evidences suggesting that, despite a

rapid initial response to bortezomib, many patients may

improve response with a longer duration of therapy. In

the APEX trial, among responders, 20% of patients

achieved the best response on cycle 8 or later (7). In the

phase IIIb study for expanded access to bortezomib (10),

the CR and VGPR rates increased with the number of

cycles from 20% at cycle 2 up to 36% at cycle 6. In our

analysis, 95% of responding patients achieved their best

response within four cycles. Extramedullary disease was

present in 19 patients (27%). Seven out of 19 responded

well to bortezomib obtaining at least a PR. This observa-

tion confirms previous reports on the efficacy of bortezo-

mib in the treatment of extramedullary localizations in

myeloma patients (12) differently from thalidomide and

lenalidomide that seem not too effective as well (13, 14).

As previously observed, in this study we confirm a

relationship between the quality of response to bortezo-

mib and clinical benefit in terms of TTP, DOR and PFS.

However, in spite of a consistent percentage of major

responses, DOR and TTP in our study were shorter than

in other studies. In SUMMIT, with an extended follow-

up of 23 months, the median TTP was 7 months and the

median DOR for patients achieving at least a PR was

12.7 months (15). In the updated analysis of the APEX

trial, the median TTP was 6.2 months and the median

DOR was 7.8 months (7). The short DOR observed in

our study is difficult to explain. The high incidence of

patients with extramedullary disease (27%) could have

affected the results. In fact, although bortezomib has

proved to be very effective in this setting of patients the

presence of extramedullary disease represents an ominous

prognostic factor.

The short DOR could also be explained by the high rate

of early discontinuation because of toxicity. In APEX

study, in fact, Richardson shows that a prolonged treat-

ment is associated with an improvement in overall quality

of response, and in prolonged DOR. Even though the rate

of discontinuation for toxicity reported in the APEX trial

(37%) is similar to that observed in our study, the median

number of cycles administered in that study was higher

(five vs. four). In the present study, the combination with

dexamethasone seems to produce an improvement of good

quality responses but not a prolongation of DOR and

TTP with respect to bortezomib alone. This could repre-

sents a not proven evidence of a lack of synergistic effect

between bortezomib and dexamethasone. Dexamethasone,

as a matter of fact, has a similar effect to bortezomib

showing a rapid antimyeloma effect but short-lived as

Bortezomib in relapsed myeloma Corso et al.

452 ª 2009 John Wiley & Sons A/S

well. So, the effect of the combination of these drugs could

be only additive.

In a multivariate analysis conducted on SUMMIT trial

(16), lower response rates were associated with older age

(>65 yr) and bone marrow plasmacytosis >50%. In our

analysis, we did not find any factor able to predict

response to bortezomib at baseline. By contrast, a reduc-

tion of at least 50% of free light chains ratio after the

first cycle was positively correlated with the possibility of

achieving a good quality response.

Among adverse events, PN was the most frequently

observed and led to dose reduction or treatment discon-

tinuation in 17 ⁄ 70 patients (24%) who presented an inco-

ercible pain. In SUMMIT and CREST (4, 5) 35% of

patients had evidence of treatment-related PN and 16%

of them discontinued treatment. In APEX study, (6) the

incidence of PN was even lower and was not influenced

by age or prior use of neurotoxic drugs (17). In our

study, the overall incidence of PN (55%) was higher but

was in line with other experiences. Badros et al. (18)

reports a 52% of incidence with a 22% of grade 3–4 PN.

Mateos et al. (19) on a cohort of elderly patients receiv-

ing bortezomib plus melphalan and prednisone as first-

line treatment observed a PN in 55% of patients (17%

grade 3–4), suggesting a correlation with age. We also

found a trend between the incidence of severe PN and

age. Despite the higher incidence, the rates and time of

resolution or improvement of PN were similar to those

reported in others studies (17), confirming that bortezo-

mib-induced PN is usually reversible.

In this study, bortezomib in combination with dexa-

methasone shows to be highly effective in

relapsed ⁄ refractory MM producing an impressive rate of

CR ⁄VGPR independently from the presence of negative

prognostic factors, but responses are short-lived. This

could be related to the quite short duration of treatment

because of the high rate of discontinuations mainly for

neurological toxicity which in our hands is neatly higher

than previously reported. As previously reported, in fact,

it is crucial to complete the scheduled cycles to guarantee

the maximum efficacy of the treatment. Thus, taking

together these items it could be conceivable to find out a

different schedule and ⁄or new combination with chemo-

therapy or new agents to reduce bortezomib-related side-

effects which can jeopardize the accomplishment of the

planned program and consequently to belittle its efficacy.

Acknowledgement

none.

Financial disclosures

none.

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