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Keywords:

  • myeloma;
  • relapsed;
  • chemotherapy;
  • bortezomib;
  • cyclophosphamide

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

A phase 2 trial was performed to study the combination of bortezomib (VELCADE®) with intermediate-dose dexamethasone (DEX), and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM were enroled to receive eight 3-week treatment cycles with bortezomib 1·3 mg/m2 on days 1, 4, 8, and 11, followed by three 5-week cycles with bortezomib 1·3 mg/m2 on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.

Treatment with single-agent bortezomib (VELCADE®; Millennium Pharmaceuticals Inc, Cambridge, MA, USA and Johnson & Johnson Pharmaceutical Research and Development LLC, La Jolla, CA, USA) at a dose of 1·3 mg/m2 effected at least partial responses (PR) in 27% of patients with relapsed and refractory multiple myeloma (MM), 38% of patients with a relapse after one to three previous therapies and 50% in patients relapsing during or after first-line therapy (Richardson et al, 2003, 2005a, 2006a; Jagannath et al, 2004). In addition, the latter study indicated a dose–response relationship with an inferior response rate (RR) of 33% with 1·0 mg/m2 of bortezomib. Median time to progression (TTP) with single agent bortezomib was superior to high-dose dexamethasone (DEX) (6·22 months vs. 3·49 months) (Jagannath et al, 2004). Overall survival (OS) in relapsed and refractory MM was 17 months (Richardson et al, 2006a). Overall survival with bortezomib was predicted by tumour burden at baseline but not by elevated β2-microglobulin (β2M) or chromosome 13 deletion (Richardson et al, 2005b). Combination with DEX in patients with either stable (SD) or progressive disease (PD) on bortezomib alone resulted in 11% to 18% additional responses (Richardson et al, 2003, 2005a). However, it has not been demonstrated whether the addition of DEX confers benefit in terms of TTP and OS compared to bortezomib alone (Kropff et al, 2005).

Conventional cytotoxic drugs may add to the efficacy of bortezomib (Bold et al, 2001; Cusack et al, 2001; Shah & Schwartz, 2001; Pink et al, 2002; Kropff et al, 2006). In MM, bortezomib has been shown to restore both melphalan- and doxorubicin-sensitivity to resistant cell lines and to synergize with melphalan in killing myeloma cells (Ma et al, 2003; Mitsiades et al, 2003). In phase 1/2 trials assessing bortezomib and melphalan or doxorubicin combinations for relapsed or refractory MM, overall response rates (ORR) of 68–73% were achieved (Orlowski et al, 2005; Berenson et al, 2006). In elderly untreated myeloma patients, bortezomib plus melphalan and prednisone appeared significantly superior to historical melphalan and prednisone alone (Mateos et al, 2006).

Cyclophosphamide (CY), an alkylating agent without cross-resistance to melphalan has a well-established activity in MM (Bergsagel et al, 1972; Brandes & Israels, 1987; Celesti et al, 1997). Haematological toxicity following CY is not cumulative and there is only rare cardiotoxicity and virtually no neurotoxicity if the drug is administered at conventional doses. CY is reasonably well absorbed following oral administration. When combined with thalidomide and DEX, oral CY yielded similar efficacy and toxicity compared to regimens employing intravenous CY for relapsed MM (Kropff et al, 2003; García-Sanz et al, 2004). In addition, a continuous oral regimen should provide the flexibility for dose modifications during treatment cycles.

In an attempt to further improve the efficacy of bortezomib/DEX, the present phase 2 trial was initiated to study bortezomib/DEX in combination with continuous low-dose CY administered orally.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients

Eligibility criteria included: primary refractory or relapsed MM requiring therapy and not considered as a candidate for immediate high-dose therapy; age 18 years or older; Karnofsky performance status ≥60%; adequate bone marrow, renal, hepatic, pulmonary, and cardiac function (haemoglobin ≥75 g/l; absolute neutrophil count ≥0·75 × 109/l; platelet count ≥50 × 109/l; creatinine clearance ≥20 ml/min; bilirubin ≤1·5 × upper limit of normal [ULN]; aspartate transaminase, alanine transaminase and alkaline phosphatase ≤2·5 × ULN). there were no restrictions regarding the number of previous regimens.

Exclusion criteria included: previous bortezomib exposure; discontinuation of prior treatment with high-dose DEX because of ≥ grade 3 DEX-related toxicity; pre-existing peripheral neuropathy of grade 2 or greater as well as any neuropathic pain; suspected cardiac amyloidosis.

A negative pre-treatment urine pregnancy test and contraception throughout treatment were required for females of childbearing potential.

The study was conducted in accordance with the Declaration of Helsinki including all current amendments, and the study protocol was approved by the local ethics committee at each participating site. Written informed consent was obtained from all patients. Data were monitored by an independent external clinical research organisation.

Study design and treatment schedule

This was an open-label, non-randomised phase 2 clinical trial conducted at 13 centres in Germany. Fifty-four patients with primary refractory or relapsed MM were scheduled to receive up to eight 3-week treatment cycles followed by up to three 5-week treatment cycles. Each 3-week treatment cycle consisted of bortezomib 1·3 mg/m2 as a single bolus i.v. twice weekly (on days 1, 4, 8, and 11). During the 5-week treatment cycles, patients received bortezomib 1·3 mg/m2 as a single bolus i.v. once weekly (on days 1, 8, 15, and 22). Within all treatment cycles, DEX 20 mg/d was given orally once daily in the morning on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous treatment at a dose of 50 mg p.o. once daily. Mandatory concurrent mediation comprised oral non-absorbable antifungal agents, antacids, prophylaxis against pneumocystis carinii infection according to institutional guidelines and monthly bisphosphonate treatment with zoledronate. When an interim safety analysis of the first 17 patients revealed that 7/17 patients had experienced herpes zoster infection, the protocol was amended to recommend for antiviral prophylaxis. Supportive treatment with colony-stimulating factors and erythropoietin as well as transfusion of platelets and red blood cells were allowed.

Dose modification and treatment delay

Adverse events were graded according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE), version 3·0 (Cancer Therapy Evaluation Program, Department of Health and Human Services, December 2003. http://ctep.cancer.gov/forms/CTCAEv3.pdf). Treatment with bortezomib and CY was withheld for ≥ grade 3 non-haematological AE (apart from neuropathy), ≥ grade 4 myelosuppression, and febrile neutropenia. Once toxicity had resolved, treatment with bortezomib and CY was resumed at a 25% reduced dose. For short-lasting myelosuppression, if only one dose of bortezomib and/or ≤7 doses (days) of CY had to be held, both drugs were continued at the same dose level. If, after bortezomib and CY had been held for up to 2 weeks, the toxicity did not resolve, then study drugs were discontinued permanently.

For neuropathy of grade 1 with pain or grade 2, bortezomib was immediately reduced by 25%. For neuropathy of grade 2 with pain or grade 3, bortezomib was withheld until resolution and reinitiated with a reduced dose of bortezomib at 0·7 mg/m2 and a once weekly schedule.

Dexamethasone was withheld for up to 2 weeks for ≥ grade 3 toxicity if the investigator considered the toxicity to be dexamethasone-related. Once the toxicity had resolved to a grade ≤2, DEX was continued at a 25% reduced dose.

Evaluation and response criteria

Baseline evaluations included physical examination, blood counts, hepatic and renal function tests, bone marrow aspirate for cytogenetic analyses (karyotyping and fluorescence in situ hybridisation) and biopsy, serum and urine protein electrophoreses, quantitation of serum immunoglobulins and urinary light chains, β2M and C-reactive protein. A chest X-ray and a complete radiological bone survey were also performed.

Safety was assessed throughout the study by physical examinations, recording of vital signs, toxicity assessments and laboratory tests (haematology, clinical chemistry). All patients that received at least one dose of the study drugs were included in the toxicity evaluation.

Patients were considered assessable for response if they had received a minimum of one treatment cycle (except in case of early progression, when the patient was considered to have PD) and had at least one follow-up myeloma assessment. The European Group for Blood and Marrow Transplantation/international Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry (EBMT/IBMTR/ABMTR) criteria were used for definition of response (Bladéet al, 1998). Briefly, a PR was defined as >50% reduction of monoclonal immunoglobulin and >90% reduction of light chain proteinuria; for a minor response (MR) the corresponding cut-off points were 25% and 50% respectively. CR required a negative immunofixation in serum and urine. PD without prior CR was determined by a ≥ 25% increase in monoclonal gammopathy or light chain proteinuria, or the occurrence of new lytic bone lesions.

Statistics

Outcome was analysed on an intention-to-treat basis. The primary study endpoint was RR, with OS, event-free survival (EFS) and toxicity analysed as secondary end points. Using a sequential Bayesian monitoring (Thall & Simon, 1994), consideration was given to stopping the trial if the ORR (≥ MR) was <60% and/or grade 3/4 toxicities (apart from alopecia and myelosuppression) were ≥ 30%. The criteria for stopping the trial were not fulfilled at any time of the study.

Event-free survival was calculated from study entry to non-response, disease progression in responders, transplantation, or death from any cause, whichever occurred first. Survival curves were estimated using the Kaplan–Meier method (Kaplan & Meier, 1958). The 95% confidence intervals (CI) were calculated by exact binominal confidence limits. Associations between categorical disease characteristics and response rate were studied with the chi-square test. P-values were considered significant when <0·05.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Patients and treatment

From April 2004 until January 2005, a total of 54 patients with primary refractory or relapsed MM were enroled onto the study and followed up until June 30th 2006. Patients’ demographics and baseline disease characteristics of all 54 patients are shown in Tables I and II.

Table I.   Patient characteristics at baseline (n = 54).
VariablePatients
n%
  1. FISH, fluorescence in situ hybridisation; ECOG PS, Eastern Cooperative Oncology Group performance status.

  2. *One patient with triclonal myeloma was not included.

Sex
 Male3565
Age
 >60 years3361
 >70 years815
Myeloma type
 IgG3565
 IgA1324
 IgM12
 Triclonal (G, A, M)12
 Light chain only47
Light chain*
 κ3667
 λ1731
ECOG PS
 03259
 11935
 236
Serum β2-microglobulin (>3·0 mg/l)3065
C-reactive protein (>3·0 mg/l)1425
Chromosome 13 deletion (FISH)1946
Bone marrow plasma cells >50%1640
Table II.   Prior antimyeloma treatment (n = 54).
VariablePatients
n%*
  1. *Because of rounding, the percentages do not add to 100.

  2. †A standard primary treatment consolidating an anthracycline/pulsed dexamethasone induction by a single or tandem autologous transplant followed by maintenance treatment was considered one regimen.

Duration of prior antimyeloma therapy
 >12 months5194
 >60 months917
No. of prior regimens†
 12343
 21324
 3713
 4713
 512
 ≥636
No. of prior high-dose therapies with autologous transplant
 01120
 12037
 22343
 ≥30 
Prior thalidomide treatment1630
Prior allogeneic transplant0 

One patient had to be withdrawn from the study prior to first study drug application because of a newly recognised exclusion criterion. Another patient succumbed to infection within 3 d of the first dose of study drugs precluding response evaluation. In two patients, no complete response assessment was available at any time.

The median number of treatment cycles with bortezomib/DEX/CY was six (median duration of treatment 4·5 months). Eighteen of the 53 patients completed 11 cycles or achieved a confirmed CR. Thirty-five patients terminated prematurely; eight patients (15%) because of PD, 17 (32%) because of AE, six (11%) because of an autologous (n = 1) or allogeneic transplant (n = 5), and four (8%) for various other reasons.

Efficacy

Of 50 patients evaluable for response, eight patients (16%) achieved a (immunofixation-negative and confirmed) CR, 33 (66%) a PR, and four (8%) a MR, resulting in an ORR (≥ MR) of 90% (Table III). Based on an intention-to-treat analysis including all 54 patients, the corresponding figures for CR, PR and MR were 15%, 61% and 7%, respectively, for an ORR of 83%.

Table III.   Confirmed response to treatment (efficacy analysis: n = 50).
 Patients
n%95% CI
Complete response8167–29
Partial response336651–79
Minor response482–19
Stable disease361–17
Progressive disease240–14

In six patients, the remission achieved enabled an autologous (n = 1) or allogeneic (n = 5) transplant. For calculation of EFS and OS, these patients were censored at the time of the transplant. Based on an intent-to-treat analysis, the median EFS was 12 months, with a median OS of 22 months (Figs 1 and 2) after a median observation time for living patients of 20 months.

image

Figure 1.  Kaplan–Meier estimates of event-free survival.

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image

Figure 2.  Overall survival as calculated by the Kaplan–Meier method.

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Prognostic factors

No single disease characteristic at baseline was consistently predictive for response to treatment, EFS, and OS (data not shown). β2M, C-reactive protein, and chromosome 13 deletion, generally considered poor prognostic factors, were not predictive of outcome with this drug combination. EFS and OS were significantly longer for patients with only one prior antimyeloma regimen (EFS 16 months vs. 9 months, P = 0·05; OS not reached vs. 13 months, P < 0·01) and no prior thalidomide exposure (EFS 16 months vs. 9 months, P = 0·05; OS not reached vs. 9 months, P = 0·0001) reflecting an earlier disease phase and greater variety of remaining treatment options for these patients. Although β2M alone was not predictive of outcome, the International Staging System (ISS) (Greipp et al, 2005) identified a high-risk group defined by β2M ≥5·5 mg/l (ISS stage III) with a median OS of 10 months for patients in stages I and II for whom OS was not reached.

Adverse events

Applying the predefined dose modification criteria there was no grade 4 anaemia or leucopenia with this combination treatment. However, 23% of patients suffered from grade 3 and 4% grade 4 infections not related to neutropenia (Table IV). Respiratory tract infection with septic course without underlying neutropenia was the cause of death in one heavily pretreated patient immediately after the first dose of study drugs. This 61-year-old patient had received four prior lines of treatment within 63 months since MM diagnosis. The incidence of grade 3/4 infections among the first 17 patients was considerably higher (47%) compared to 11% among the remaining 36 patients treated after antiviral prophylaxis was recommended.

Table IV.   Grade 3 or 4 adverse events regardless of relation to study drug treatment (n = 53).
Adverse event (maximum grade per patient)Grade 3Grade 4
n%n%
  1. AST, serum aspartate transaminase; ASL, serum alanine transaminase.

Anaemia590 
Leukocytopenia11200 
Infection101924
Herpes zoster61124
Thrombocytopenia18341019
Bleeding120 
Neuropathy71724
Fatigue5936
Constipation0 0 
Mood alteration120 
Diarrhoea120 
Liver, AST/ASL120 
Renal failure1212
Hyperglycaemia0 0 
Endokrin0 12
Cardiovascular events0 0 
Hypotension360 
Dyspnea240 
Oedema240 
Venous thromboembolic disease0 0 
Myopathy120 
Mucositis120 
Skin120 

Twenty-five per cent of patients received red cell transfusion support, predominately (12/13) during the first three treatment cycles. After cycle three, only one patient required transfusions. Two patients received additional erythropoietin.

During the 3-week treatment cycles platelet counts declined from day 1 to day 11 by 37% and to day 16 for an additional 8% resulting in a median platelet reduction during treatment of around 45% (95% CI, 25–52%)(Fig 3). During subsequent 5-week cycles with once weekly bortezomib injections, the median platelet reduction reached 8%. Seventeen percent of patients experienced transient grade 4 thrombocytopenia at least once and 9% received platelet support; there was only one clinical bleed in a patient with severe sepsis and disseminated intravascular coagulation. Grade 4 thrombocytopenia occurred predominately on day 16 of the first three treatment cycles (67% of episodes). With 10% of events the risk of grade 4 thrombocytopenia was highest during cycle 2 and remained between 3% and 5% during cycles 3–6; beyond cycle 6 no grade 4 thrombocytopenia was observed.

image

Figure 3.  Median platelet counts over time (11 treatment cycles).

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Treatment-emergent neuropathy was estimated to be grade 1 in 17%, grade 2 in 28%, and grade 3 in 17% of the patients. In addition, two patients (4%) with a segmental paralysis during herpes zoster were documented to have grade 4 neurotoxicity with a severity possibly related to a pre-existing grade 1 to 2 neuropathy. There was no grade 4 neuropathy without concomitant herpes zoster. In line with recently published data (Richardson et al, 2006b), neuropathy was not related to prior thalidomide or vincristine exposure, as about 30% each of patients with or without neuropathy had received previous treatment with these drugs. Neuropathy and fatigue were the dominant reasons for bortezomib discontinuation.

Twelve out of 53 patients experienced varicella-zoster reactivation with 9/12 episodes occurring during the first three treatment cycles. Herpes zoster was of grade 2 severity in four patients, grade 3 in six patients and grade 4 in two patients. After seven out of the first 17 patients (41%) had developed herpes zoster, prophylactic antiviral treatment was recommended. Subsequently, five out of the 36 remaining patients developed herpes zoster. Notably, four of these five patients had not received antiviral prophylaxis.

Nineteen out of 53 patients (36%) required a dose reduction of bortezomib, 13 to 1·0 mg/m2 and 6 to 0·7 mg/m2. Finally, 16 patients permanently stopped bortezomib treatment either because of incomplete resolution of toxicity following treatment interruption or because of recurrent toxicity even after dose or schedule modification as per protocol. The predominant AE necessitating bortezomib dose modification was neuropathy in 14/19 patients. Five out of 53 patients (9%) terminated treatment with DEX mainly for myopathy (n = 3) and continued with bortezomib/CY. Six patients (11%) had a CY dose reduction for recurrent myelosuppression. Overall, 17/53 patients terminated the study prematurely with ≥ grade 3 infections and neuropathy constituting the most frequent reasons (four patients each).

There was no apparent pulmonary, cardiac or hepatic toxicity with this drug combination and no venous thromboembolic event. Moreover, the combination of bortezomib/DEX/CY with monthly zoledronic acid infusions appeared to be safe and well tolerated as there were no obvious AEs related to zoledronic acid according to the investigators’ assessments.

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Based on preclinical studies, bortezomib has been attributed the potential of chemosensitization and overcoming resistance against cytotoxic drugs (Ma et al, 2003; Mitsiades et al, 2003). Phase 1/2 studies combining bortezomib with melphalan or doxorubicin for relapsed MM have shown encouraging antimyeloma activity even in patients with prior exposure to these drugs (Orlowski et al, 2005; Berenson et al, 2006). This study aimed to define the impact of CY when combined with bortezomib and DEX for relapsed or refractory MM. We chose continuous oral CY based on the experience by García-Sanz et al (2004), who reported encouraging short as well as sustained long-term efficacy and low toxicity when this CY schedule was combined with DEX and thalidomide. A continuous CY schedule should permit dose modifications within treatment cycles (e.g. for myelosuppression). For this reason, the investigators did not feel it was necessary to start with a formal phase 1 evaluation of this combination.

The application of this drug combination achieved a high rate of true immunofixation-negative and confirmed CRs according to EBMT criteria. As we did not exclude patients with advanced myeloma ≥ 4th relapse, our collective cannot be directly compared to the patients participating in the Assessment of Proteasome Inhibition for Extending Remissions (APEX) study (Richardson et al, 2005a). Accepting this limitation, a fixed combination of bortezomib with DEX and CY seemed to increase response rates as well as time to progression and EFS, compared to single agent treatment with bortezomib. Comparisons of the current study regimen with doxorubicin- (Orlowski et al, 2005) and melphalan- (median progression-free survival 8 months) (Berenson et al, 2006) containing drug combinations with bortezomib for relapsed MM are hampered by the phase 1/2 design of the latter trials potentially treating some patients at suboptimal drug doses.

In this trial EFS and OS were superior for patients receiving this drug combination as second-line treatment and without prior thalidomide exposure. In line with data from the SUMMIT trial, addition of bortezomib to DEX and CY overcame the poor prognostic impact of chromosome 13 deletion (Richardson et al, 2003).

Adverse events of grade 3 or 4 in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Notably, no deep vein thrombosis was seen. Infections were not related to leucopenia. This suggests that the incidence of ≥ grade 3 infections may have been influenced by the potentially immunosuppressive combination of bortezomib with DEX. In line with the experience on bortezomib plus melphalan and prednisone in elderly untreated patients with MM (Mateos et al, 2006), prophylactic antiviral treatment appeared to prevent herpes zoster. Moreover, the considerable reduction in bacterial infections (from 47% to 11%) following the introduction of prophylactic antiviral treatment indicates that viral infections could pave the way for serious bacterial infections in relapsed MM.

Based on pretreatment complete blood counts (CBC) prior to each bortezomib dose, thrombocytopenia has been recognised to be transient and cyclical (Lonial et al, 2005). However, the true platelet nadir, expected to occur between days 11 and 22 of each 3-week treatment cycle, was not known. In this study, a further drop of median platelets counts was detected by day 16 ± 1 during each 3-week treatment cycle. Consequently, grade 4 thrombocytopenia occurred in 17% of the patients mainly around day 16. It is to be noted that day 16 platelet counts were not reported in previous studies. However, the lack of clinically significant bleeding episodes in this study supports the currently established surveillance schedule as well as published recommendations for dose modification due to thrombocytopenia for myeloma patients on the bortezomib combination used in this study.

Despite rigorous application of the classical bortezomib-derived dose reduction algorithm, grade 3/4 neuropathies appeared to be slightly increased in this study when compared with previous reports (Richardson et al, 2003; Jagannath et al, 2004; Richardson et al, 2005a; Mateos et al, 2006; Richardson et al, 2006b), although they may have been attributable, at least in part, to herpes zoster infections.

Given the efficacy of prophylactic antiviral treatment (parallel reduction in herpes zoster and bacterial infections potentially secondary to viral), which is considered to be mandatory with this drug combination, one may conclude that the bortezomib/DEX/CY combination considerably improves RR and EFS compared to single agent treatment with bortezomib without significant increase in severe AE. These results have prompted our current study of this three-drug combination in a multicentre trial on first-line treatment of MM patients.

Acknowledgements

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The authors thank Astrid Kruse for excellent patient care and data collection support. This study was supported in part by research funding from ORTHO BIOTECH DIVISION OF JANSSEN CILAG GmbH; and by NOVARTIS ONCOLOGY, Germany.

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  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
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