Initial results of a German clinical trial con­firm pre­vi­ous find­ings that sub­cu­ta­ne­ous (under-the-skin) injections of Velcade for the treat­ment of myeloma lead to fewer side effects – but similar over­all response rates – com­pared to intra­ve­nous (IV) infusions of the drug.

The trial results also indicate, however, that IV adminis­tra­tion of Velcade may lead to deeper treat­ment responses when patients are given the drug for a limited number of treat­ment cycles.

The German trial is notable not just because it is the largest study to date that has directly compared sub­cu­ta­ne­ous and IV Velcade. It also is the first study of its kind to be carried out in newly diagnosed myeloma pa­tients. A pre­vi­ous study that compared the two methods of admin­istering Velcade was conducted with re­lapsed myeloma patients.

In addi­tion, the German study compared sub­cu­ta­ne­ous and IV Velcade when used as part of two different multi-drug treat­ment regi­mens. One of those regi­mens is the commonly used com­bi­na­tion of Velcade, cyclo­phosphamide, and dexa­meth­a­sone (VCD, CyBorD).

In the pre­vi­ous comparative study involving re­lapsed patients, treat­ment initially was with Velcade alone. Dexamethasone could be added to the Velcade if, after four initial cycles of treat­ment, patients did not achieve a com­plete response.

The results of the German trial also indicate that responses to treat­ment with sub­cu­ta­ne­ous and IV Velcade were similar in three patient subgroups the researchers analyzed regularly throughout their study: patients with chromo­somal ab­nor­mal­i­ties asso­ci­ated with higher-risk disease; patients with reduced kidney function; and patients with Stage III disease at diag­nosis.

The new trial results are not, however, an unequivocal victory for sub­cu­ta­ne­ous Velcade. Although response rates for sub­cu­ta­ne­ous and IV Velcade were similar in the trial, the share of patients achieving deeper re­sponses was higher in patients treated with IV Velcade.

For example, among the patients in the trial who received the VCD treat­ment regi­men, 42 per­cent of those who received IV Velcade achieved at least a very good partial response, compared to 29 per­cent of the patients who received sub­cu­ta­ne­ous Velcade.

This difference in depth of response was not seen in the earlier comparative trial with re­lapsed patients. In that study, depth of response was almost exactly the same in both the sub­cu­ta­ne­ous and IV patients.

It is possible that the difference in depth of response in the German trial was due to the fact that patients in the trial received only three cycles of each of the tested treat­ment regi­mens. Had the patients received addi­tional cycles of treat­ment, the German researchers note, there may not have been much difference in depth of response.

In the earlier comparative trial, the re­lapsed patients participating in the study could receive up to 10 cycles of ther­apy.  Other studies also have examined the efficacy and tolerability of sub­cu­ta­ne­ous Velcade, although they have not included comparison groups of patients treated with IV Velcade.  These other studies, the German researchers add, also involved more than three cycles of ther­apy, and their results suggest that sub­cu­ta­ne­ous Velcade does not result in less depth of response than IV Velcade.

Significance Of The New Study

“The German study’s results regarding potential differences in depth of response between sub­cu­ta­ne­ously and intra­ve­nously admin­istered bor­tez­o­mib [Velcade] as part of multi-drug com­bi­na­tions are really quite interesting,” Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston told The Beacon. “The results may in fact have some significance in clinical practice.”

“IV admin­istra­tion is known to lead to higher peak concentrations of bor­tez­o­mib in a patient’s blood, as compared to sub­cu­ta­ne­ous admin­istra­tion,” Dr. Richardson went on to explain. “The higher concentration has resulted in more effective treat­ment of plasmacytomas in preclinical models, and this may explain the greater efficacy of IV, rather than sub­cu­ta­ne­ous, bor­tez­o­mib sometimes seen in patients with ad­vanced myeloma and extramedullary plasmacytomas.”

“IV bor­tez­o­mib therefore could be of importance,” Dr. Richardson elaborated, “in select patients who do not initially benefit from sub­cu­ta­ne­ous admin­istra­tion – especially those with refractory, bulky disease requiring a com­bi­na­tion ap­proach."

That said, Dr. Richardson also agreed with the authors of the German study, who noted that, because sub­cu­ta­ne­ous admin­istra­tion of Velcade results in significantly fewer serious side effects than IV admin­istra­tion, it should allow the drug to be given for a greater number of treat­ment cycles in many patients. This, in turn, could allow for deeper responses over time than were seen in the new study, with its fixed number of three initial treat­ment cycles.

Background

Velcade ^[1] (bor­tez­o­mib) was first approved by the U.S. Food and Drug Administration as a treat­ment for multiple myeloma in 2003.  When it was approved, it was recommended that the drug be admin­istered via intra­ve­nous infusion, and this was the standard way of admin­istering Velcade for many years.

Interest in admin­istering Velcade sub­cu­ta­ne­ously, which would be more convenient than IV admin­istra­tion, led in 2006 to the organization of a small trial in France to compare the two methods of admin­istra­tion.

The encouraging results of that small trial prompted a larger, Phase 3 comparative trial that was carried out in several European countries. That trial, which involved re­lapsed myeloma patients, found that sub­cu­ta­ne­ous and IV admin­istra­tion of Velcade resulted in similar response rates, but sub­cu­ta­ne­ous admin­istra­tion caused fewer serious side effects.

The results of the European study led the FDA to update Velcade’s pre­scrib­ing in­­for­ma­tion in 2012 to specify that the drug can be admin­istered either sub­cu­ta­ne­ously or intra­ve­nously (see related Beacon ^[2] news).

The results of the European study also led to a change in the design of an ongoing German clinical trial designed to compare two Velcade-based treat­ment regi­mens given to newly diagnosed myeloma patients prior to a stem cell trans­plan­ta­tion. The two regi­mens were:

• Velcade, cyclosphosphamide (Cytoxan), and dexamethasone (Decadron) – commonly referred to as either VCD or CyBorD, and
• Velcade, doxorubicin (Adriamycin), and dexamethasone – commonly referred to as PAd,

Velcade initially was admin­istered intra­ve­nously to patients recruited for the German trial. After results of the European study com­par­ing IV and sub­cu­ta­ne­ous Velcade became available, the organizers of the German trial switched to admin­istering Velcade sub­cu­ta­ne­ously to all remaining patients recruited into the trial.

This arbitrary change in the trial’s design has made it possible for the German researchers to directly compare, for the first time, the efficacy and safety of sub­cu­ta­ne­ous and IV Velcade in newly diagnosed multiple myeloma patients.

Study Design

Between July, 2010 and November 2013, researchers recruited 604 newly diagnosed, trans­plant-eligible multiple myeloma patients at more than 100 trans­plant and treat­ment centers in Germany. Patients with AL amyloidosis or mod­er­ate to severe periph­eral neu­rop­athy were not eligible to par­tic­i­pate in the trial.

The primary objective of the trial was to compare the response rates and pro­gres­sion-free survival of the VCD and PAd treat­ment regi­mens when used prior to a stem cell trans­plant.

Patients were ran­domized to receive three cycles of one of the fol­low­ing treat­ment regi­mens:

• VCD - 1.3 mg/m² of Velcade on days 1, 4, 8, and 11; 900 mg/m² of cyclophosphamide on day 1; and 40 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 in a 21-day treatment cycle; or
• PAd - 1.3 mg/m² of Velcade on days 1, 4, 8, and 11; 9 mg/m² of doxorubicin on days 1-4; and 20 mg of oral dexamethasone on days 1-4, 9-12, and 17-20 in a 28-day treatment cycle.

Just under half the patients in the trial (49 per­cent) received Velcade as sub­cu­ta­ne­ous injections during their treat­ment. The remaining patients had their Velcade admin­istered intra­ve­nously.

Study Results - Efficacy

The study results show that there was no significant differences in the over­all responses rate among patients receiving sub­cu­ta­ne­ous or intra­ve­nous Velcade.

In the VCD treat­ment group, 78 per­cent of patients who received IV Velcade had at least a partial response, compared to 82 per­cent of patients who received sub­cu­ta­ne­ous Velcade. In the PAd treat­ment group, the difference was even smaller; 73 per­cent of patients who received intra­ve­nous Velcade responded, compared to 71 per­cent of patients who received sub­cu­ta­ne­ous Velcade.

Further analysis showed that the over­all response rate also was similar for IV and sub­cu­ta­ne­ous Velcade in the three patient subgroups examined by the researchers in their study: patients with higher-risk chromo­som­al ab­nor­mal­i­ties; patients with reduced kidney function; and patients with Stage 3 disease at diag­nosis.

However, IV admin­istra­tion did typically lead to deeper responses to treat­ment.  For example, more patients treated with IV Velcade during the VCD treat­ment regi­men had a very good partial response or better than those treated with the same regi­men, but who received sub­cu­ta­ne­ous Velcade (42 per­cent versus 29 per­cent).

Likewise, 27 per­cent of the VCD patients who received IV Velcade achieved a near-complete or com­plete response, compared to 14 per­cent of the VCD patients who received sub­cu­ta­ne­ous Velcade.

This pattern of IV Velcade leading to deeper responses than sub­cu­ta­ne­ous Velcade also was seen for the patients who were treated with the PAd regi­men, although not to as significant an extent.

In addi­tion, the pattern typically was seen in each of the three patient subgroups mentioned earlier, for both treat­ment regi­mens. In most cases, however, these differences were not statistically significant.

Data on pro­gres­sion-free and over­all survival were not reported in the current study. The researchers point out that longer follow-up is necessary to provide meaningful esti­mates of those out­comes.

Study Results – Safety & Tolerability

The study authors also found that fewer patients receiving sub­cu­ta­ne­ous Velcade (55 per­cent) ex­peri­enced mod­er­ate to severe side effects than patients receiving intra­ve­nous Velcade (65 per­cent).

In particular, fewer patients receiving sub­cu­ta­ne­ous Velcade had in­fec­tions (19 per­cent, versus 25 per­cent for patients receiving intra­ve­nous Velcade), gastro­in­tes­ti­nal disorders (4 per­cent versus 10 per­cent), and metabolism and nutrition disorders (5 per­cent versus 13 per­cent).

The share of patients who developed mod­er­ate to severe periph­eral neu­rop­athy (pain and tingling in the extremities) also was lower among patients receiving sub­cu­ta­ne­ous Velcade compared to those receiving intra­ve­nous Velcade (8 per­cent versus 12 per­cent).

There was no difference, however, between the two forms of Velcade admin­istra­tion in how often patients in the study ex­peri­enced particularly severe side effects (“serious adverse events”).  Such side effects occurred in 28 per­cent of the patients who received sub­cu­ta­ne­ous Velcade and 29 per­cent of the patients who re­ceived IV Velcade.

For more in­­for­ma­tion, please see the study by Merz, M. et al., “Sub­cu­ta­ne­ous versus intra­ve­nous bor­tez­o­mib in two different induction ther­a­pies for newly diagnosed multiple myeloma: interim analysis from the pro­spective GMMG-MM5 trial,” in Haematologica, April 3, 2015 (full-text PDF ^[3]).