Apex trial multiple myeloma

A companion crossover study, which offered single-agent bortezomib initially only to patients with progressive disease PD on high-dose dexamethasone, was opened to all patients randomized to high-dose dexamethasone. In this updated analysis, we report whether bortezomib continues to provide improved survival compared with high-dose dexamethasone.

Other updated efficacy parameters for the bortezomib arm are reported. The relationship between duration of response DOR and quality of response as measured by M-protein reduction was analyzed, as was the relationship between DOR and time to first response TTR.

In addition, we report an exploratory analysis comparing patients who initially received bortezomib on APEX with those who first received high-dose dexamethasone and crossed over to receive bortezomib on the companion study. Approval was obtained from the institutional review boards of all participating institutions Document S1, available on the Blood website; see the Supplemental Materials link at the top of the online article.

Informed consent was obtained in accordance with the Declaration of Helsinki. APEX study details have been reported. Patients were assessed for disease status and survival every 3 weeks for 39 weeks.

Follow-up occurred every 6 weeks until PD, then every 3 months for survival. Patients on the companion crossover study received single-agent bortezomib as administered according to the dose and schedule of the bortezomib treatment arm of the APEX study. Updated analyses of survival of patients originally randomized to bortezomib and dexamethasone were performed.

Updated efficacy analyses were performed for all patients in the bortezomib arm, following treatment completion in 85 patients still receiving bortezomib at initial analysis the dexamethasone arm was halted; additional analysis was not possible. Response and survival with single-agent bortezomib were compared between patients who crossed over to bortezomib after PD on dexamethasone and patients initially randomized to bortezomib.

Patients' baseline characteristics have been described. Median OS was These results show that, with longer follow-up and despite substantial crossover from the high-dose dexamethasone arm, bortezomib continues to demonstrate improved survival compared with dexamethasone. Figure 1 A also shows survival for a subset of dexamethasone patients who crossed over to bortezomib after PD within 6 months. Because baseline characteristics are not matched with bortezomib patients, the exploratory analysis was conducted to compare earlier versus later bortezomib.

Bortezomib continues to demonstrate improved survival compared with high-dose dexamethasone, and overall quality of response continues to improve with longer bortezomib treatment beyond initial response. Median time to progression, response rate, median time to first response, and median duration of response in patients on the bortezomib arm in this updated analysis versus the initial analysis of bortezomib and high-dose dexamethasone.

Median length of bortezomib therapy was 6 cycles, while responding patients received a median of 10 cycles protocol-specified 8 cycles plus 2 additional maintenance cycles. Therefore, longer therapy beyond rapid initial responses led to continued improvement in overall quality of response.

This, combined with the finding that higher quality of response was associated with longer duration of response, supports extended treatment with bortezomib beyond initial response in patients tolerating therapy. Where they occurred, only slight differences were seen in incidences of commonly reported adverse events between updated and initial analyses. In the exploratory analysis of matched pairs of patients receiving bortezomib earlier on APEX compared with later on companion study following PD on high-dose dexamethasone , median OS was The longer survival seen in patients receiving bortezomib earlier, together with data from additional APEX analyses showing greater efficacy with bortezomib at first relapse versus later salvage therapy, 1 , 7 , 8 indicates that, as might be expected, earlier use of bortezomib in relapsed MM may offer greater benefit.

Bortezomib-based combinations are also being investigated with the aim of improving outcomes, with promising results to date.

In conclusion, bortezomib continues to demonstrate superior survival to high-dose dexamethasone in patients with relapsed MM following 1 to 3 prior therapies, confirming the substantial activity of bortezomib as a single agent and further supporting its study both earlier in the disease course and in combination regimens. Due to its novel mechanism of action, bortezomib has been shown to induce responses in previously refractory patients including those with poor risk cytogenetics , and results in an increased progression free and overall survival in relapsed patients when compared with dexamethasone treatment alone.

It is well tolerated and can be administered in the outpatient setting with manageable toxicities. Peripheral neuropathy is the most common dose limiting toxicity and thrombocytopenia can generally be managed with platelet transfusions without reducing or omitting doses.

Much has been learnt about multiple myeloma pathobiology over the last decade. We have elucidated many of the important growth and survival pathways and understand in some detail the relationship between the plasma cell and the bone marrow microenvironment. The current emphasis of research is to translate these findings into the clinic and to develop novel targeted treatment approaches to improve patient outcome. Inhibition of the proteasome represents a completely new approach to the treatment of myeloma with studies demonstrating that this strategy is effective at killing myeloma cells that are otherwise resistant to conventional lines of therapy.

Bortezomib is the first proteasome inhibitor to be approved for the treatment of myeloma and represents a step forward in the management of these patients. Phase III data from the landmark APEX trial demonstrate a significant survival advantage in patients with relapsed multiple myeloma treated with bortezomib compared with those treated with dexamethasone alone Richardson et al a. Since its approval by the US Food and Drug Administration FDA in there has been rapid clinical development and it is now approved in over 50 countries worldwide.

This review aims to discuss the data supporting the use of bortezomib in the treatment of myeloma, as well as highlighting some of the more practical issues surrounding its use in the clinical setting. Bortezomib, formerly known as PS, is a boron containing molecule that specifically and reversibly inhibits the threonine residue of the 26S proteasome, an enzyme complex that plays a key role in the cell by regulating protein degradation in a controlled fashion.

Proteins that are no longer required, including those involved in cell cycle control, apoptosis and cell signaling, are tagged with ubiquitin which directs them to the proteasome which subsequently degrades them. This process maintains the balance of inhibitory and stimulatory proteins involved in cell cycle, thus inhibition of the proteasome results in a loss of the tight control of the process with a build up of cell cycle and regulatory proteins leading to cell death Adams et al ; Adams Recent reports also suggest that bortezomib may disregulate intracellular calcium metabolism resulting in caspase activation and apoptosis Landowski et al Bortezomib has potential as a chemotherapeutic agent in many different tumor types as proteasomes are present in all eukaryotic cells; however it also has a number of myeloma specific effects.

Other effects in myeloma include inhibition of angiogenesis, inhibition of DNA repair and impairment of osteoclast activity Rajkumar et al Tumor cells appear to be more sensitive to the effects of proteasome inhibition than normal cells due to a loss of checkpoint mechanisms occurring during tumorgenesis; this means that normal cells can usually recover as the inhibition is transient and reversible.

In the CREST study, 54 patients with relapsed myeloma following one line of therapy were randomized to receive bortezomib at either 1. The Assessment of Proteasome inhibition for EXtending remissions APEX trial was a randomized phase III trial set up to compare bortezomib with high dose dexamethasone in patients with multiple myeloma who had relapsed after one or more therapies.

The results showed a significant survival benefit in the bortezomib group and the trial was terminated early with the dexamethasone patients crossing over to the bortezomib arm Richardson et al a. Response rates were higher in those who had only received one prior line of therapy. It can be concluded from this phase III data that bortezomib is superior to high dose dexamethasone as second line treatment for relapsed myeloma.

Based on the results of these three trials in May , the FDA approved bortezomib for use in patients with relapsed and refractory myeloma who had received 2 or more prior therapies, and in April the European Commission approved its use as a second-line treatment in patients with multiple myeloma who have already undergone or are unsuitable for bone marrow transplantation.

Bortezomib is usually given on an outpatient basis as a short intravenous infusion on days 1, 4, 8, 11 of a 3 weekly cycle.

The 72 hour gap between infusions is important to allow recovery of the proteasome inhibition in the normal cell. The 10 day treatment-free period allows cell recovery and prevents excessive side effects. A total of up to 8 cycles may be given depending on response and toxicities. On the basis of laboratory data showing an additive anti-proliferative effect Hideshima et al , bortezomib was combined with dexamethasone at a dose of 20 mg on the day of and day after each injection.

Although the initial phase II trials were designed so that dexamethasone was added in when there was failure to respond to 2 cycles of single agent therapy, it can be argued given the synergistic effect of the combination of bortezomib and dexamethasone, that dexamethasone should be given to all patients who are able to tolerate it from the start of treatment.

This suggests that if patients are not responding to treatment after 4 courses of therapy 2 as single agent and 2 with the addition of dexamethasone then therapy should be changed. Based on data from the SUMMIT trial, the most common side effects are fatigue and weakness, gastrointestinal disturbances including nausea and vomiting, diarrhea, constipation , thrombocytopenia and peripheral neuropathy Richardson et al It is recommended that bortezomib should be withheld at the onset of grade 3 non-hematological or grade 4 hematological toxicity, until the toxicity resolves and then treatment restarted at a lower dose.

Although gastrointestinal disturbances and fatigue are the most common side effects, peripheral neuropathy and thrombocytopenia are the most problematic and clinically significant and are therefore discussed in further detail below. In most instances the neuropathy improves or resolves once treatment is completed over a median of 3 months San Miguel et al Based on experience from the phase II single agent trials a number of recommendations for dose modification in patients experiencing peripheral neuropathy as graded by the National Cancer Institute common terminology criteria for adverse events have been made.

These are summarized in Table 1 NCI Abbreviations: ADL, activities of daily living. Patients with pre-existing neuropathy may experience worsening symptoms during treatment with bortezomib and should therefore be monitored closely; however pre-existing neuropathy, for example from previous thalidomide, should not in itself preclude the use of bortezomib. Supportive measures include the use of agents such as gabapentin and amitryptiline, opiates, and referral to a specialist pain service.

It is important to ensure vitamin B and folate levels are normal and not exacerbating the neuropathy. The actual mechanism of nerve damage is not known and has been difficult to establish as many patients in the trials had preexisting neuropathy. Hypotheses range from damage to the peripheral nerve blood supply because of its anti-angiogenic effect, a possibility of an increased inhibitory effect on the proteasome within nerve endings and a dose related disruption of normal homeostasis of cytosolic proteins involved in axonal transport EMEA They can be added to dose-modification schedules of bortezomib, but it is worth remembering that patients with sensory neuropathy induced by bortezomib could be resistant to them.

The choice of medication in an individual case may depend on many factors. Among them potential for adverse events AEs , drug interactions, and risk of abuse have to be taken into consideration. In general, data concerning safety, efficacy and tolerability of pain relief therapy have to be recognized with caution.

It should be a rule to introduce small doses with subsequent slow titration to effective dosage. In case of an AE the therapy needs to be discontinued. Some neuropathic patients treated with one class of pain relief medication could respond while other patients could fail to respond.

A partial response to selected first-line therapy can be changed to a complete response by adding another first-line therapy combination therapy. Nevertheless, the disadvantage of combination therapy comes from an increased risk of AEs.

The data concerning the period within which the pain relief treatment should be maintained at a stable level is difficult to establish. It lasts 4 to 6 weeks, and thereafter slow lowering of dosage is preferred. Gabapentin should be initiated at low doses — mg 3 times a day with gradual increase until pain relief or dose-limiting AE.

The increase by — mg 3 times daily should be performed every 7 days. Maximal dose is as high as mg per day. Pregabalin — beginning dosage has been established as 50 mg 3 times daily or 75 mg twice daily.

Both have been used as antiepileptic drugs, but they also possess high pain relief potential. Renal impairment needs dosage modification in relation to creatinine clearance. Side effects such as daytime sedation, somnolence, dizziness, gait ataxia, and gastrointestinal symptoms are mostly observed. Duloxetine — initial dose 30 mg per day should be increased to 60 mg within a week.

Venlafaxine — starting dosage Venlafaxine can rarely trigger cardiac arrhythmias and arterial blood hypertension. Tricyclic antidepressants TCAs. This class of medications is very effective in alleviating pain syndromes. Nevertheless, numerous AEs limit their usage. Because of cardiotoxicity and the negative impact on cognitive functions they should not be recommended to older patients.

They are contraindicated in glaucoma increase in intraocular hypertension. They exert anticholinergic side effects and also trigger psychotic episodes.

Nortriptyline should be initiated at a low dose of 10 or 25 mg once a day in late evening. The dose, if necessary, may be increased by 10 or 25 mg every 7 days. The effective dose if tolerated is as high as mg daily. Amitriptyline — the initial dosage and titration are the same as with nortriptyline.

AEs are much more severe and appear with higher incidence in comparison with AEs of nortriptyline. Topical lidocaine. No more than 3 patches daily should be adhered to the painful region for no more than 12 hours. There are no data indicating that more patches applied to the skin give better pain relief. Treatment lasts for 3 weeks.

Opioid analgesics. Recently, this class of first line-therapy has not been recommended for the treatment of neuropathic pain unless the other first-line regimens are effective. Long-term opioid therapy develops physical and psychological dependence. Always sedation, constipation and nausea accompany. Initial doses should be low; gradual titrating and reduction needs time.

For pain relief, tramadol has been used extensively. Initial dosage should be as low as 50 mg once or twice a day. Titration up to mg daily can be achieved by increase of the daily dose by 50 to mg every 3 to 7 days. In older patients, at age 70 or more with renal and hepatic damage lower dosage up to mg per day is recommended. In summary the authors emphasize that despite the high risk of BIN currently introduced algorithms of dose-limiting schedules have been successful in pain relief.

This allows therapy to be continued, which results in a longer life span without deterioration of daily living for MM patients.

It is also of significance that contrary to the previously used regimens in plasmacytic dyscrasias including alkylating agents, among them melphalan, bortezomib therapy does not increase the risk for developing secondary neoplasms [ 36 ]. National Center for Biotechnology Information , U. Journal List Contemp Oncol Pozn v. Contemp Oncol Pozn. Published online Oct Author information Article notes Copyright and License information Disclaimer. Corresponding author. This article has been cited by other articles in PMC.

Abstract Neurotoxicity towards the peripheral nervous system which appears clinically in the form of painful neuropathy is an essential dose-limiting factor during the treatment of multiple myeloma. Keywords: multiple myeloma, bortezomib, bortezomib induced neuropathy. Introduction There is growing evidence that introduction of bortezomib to the treatment of multiple myeloma MM not only results in longer survival but also, on the basis of comparative studies with different pharmacological regimens, enhances the percentage of MM patients with complete or partial responses [ 1 — 3 ].

Pathogenesis of bortezomib-induced neuropathy The mechanisms involved in the toxic action against peripheral nerves are not fully understood. Clinical findings in bortezomib-induced neuropathy The assessment of BIN is based mainly on an interview and neurological examination.

Diagnostic procedures in monitoring of bortezomib-induced neuropathy Detailed interview together with clinical examination, with special attention paid to the presence of symptoms and signs of small-fibre neuropathy, is the first step in the diagnosis of BIN. Previously reported results from the APEX study demonstrated superior efficacy, in terms of higher overall response rate and CR rate, and longer median TTP and median OS, with bortezomib compared with dexamethasone. Bortezomib treatment resulted in higher response rates than dexamethasone in all four renal subgroups.

Taken together, the data from this subgroup analysis suggest that treatment with bortezomib partially overcomes the poor prognosis conferred by renal impairment. However, comparisons of OS between the subgroups should be made with caution given the confounding factors of crossover to bortezomib from the dexamethasone arm and the availability of a number of active salvage regimens for subsequent therapy.

The results of this subgroup analysis also indicate that the presence of renal impairment does not result in marked changes in the safety profile of bortezomib in patients with MM and does not raise any new safety concerns.

This is as expected, given the findings of a pharmacologic study of bortezomib in adult cancer patients with impaired renal function, which indicated that bortezomib clearance is independent of renal function. Consequently, the median duration of bortezomib therapy was similar across subgroups.

These data show that the efficacy of bortezomib is not compromised by a specific need for reduction of dose in patients with renal impairment. The findings of this analysis of the randomized APEX study regarding the efficacy and safety of bortezomib in patients with renal impairment are supported by other studies of bortezomib alone or in combination, in these patients. Bortezomib has been shown to be well tolerated in adult cancer patients regardless of CrCl in an NCI-sponsored pharmacological study.

Most of these studies involve small series of selected patients. However, the present analysis has been conducted using a very large series of unselected patients, enabling the evaluation of the efficacy of bortezomib in patients with varying degrees of renal impairment. Moreover, the design of the study enabled comparison of the efficacy of bortezomib with that of high-dose dexamethasone, which has been considered as a gold standard for the treatment of MM patients with renal failure.

In conclusion, the present analysis represents to the best of our knowledge the first study on the prognostic influence of renal function within the setting of a randomized trial and demonstrates that bortezomib is active and well tolerated in patients with relapsed MM following 1—3 prior therapies and with varying degrees of renal impairment.

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