Initial results of an ongoing Phase 2 clinical trial show that Kyprolis in combina­tion with Revlimid and low-dose dexa­meth­a­sone may be effective and safe in high-risk smol­der­ing multiple myeloma patients.

Specifically, the results show that all patients responded to the com­bi­na­tion ther­apy, with 75 per­cent of patients achieving at least a near complete response.

Progression-free or over­all survival results are not yet available, though, to indicate whether the com­bi­na­tion ther­apy delays pro­gres­sion to myeloma or extends over­all survival.

Dr. Ola Landgren from the U.S. National Cancer Institute and National Institutes of Health presented the findings at the Inter­na­tional Myeloma Workshop (IMW) in Kyoto, Japan, this past Saturday.

Although Dr. Landgren and his colleagues are very pleased with the high response rates seen thus far in their study, Dr. Landgren told The Beacon that it is still too early to recommend active treat­ment of smol­der­ing myeloma other than in clinical trials.

Background

Smoldering, or asymptomatic, multiple myeloma is a precursor to multiple myeloma in which the patient experiences none of the symp­toms typically asso­ci­ated with active (symptomatic) multiple myeloma (ele­vated cal­cium levels, kidney failure, anemia, or bone lesions).

Although smol­der­ing myeloma patients are at a higher risk of devel­op­ing active myeloma than the general public, the current standard of care is to monitor smol­der­ing myeloma patients and to begin treat­ment only when their disease progresses to multiple myeloma.

Results of a recent Spanish study, however, have shown that smol­der­ing myeloma patients with a high risk of progressing to multiple myeloma may benefit from early treat­ment. In particular, the results showed that Revlimid (lena­lido­mide) in com­bi­na­tion with dexamethasone (Decadron) delayed disease pro­gres­sion and extended over­all survival of high-risk smol­der­ing multiple myeloma patients (see related Beacon news).

Kyprolis (car­filz­o­mib) was approved in July by the U.S. Food and Drug Admin­is­tra­tion for the treat­ment of multiple myeloma patients who have received at least two prior ther­a­pies, including Velcade (bor­tez­o­mib) and an immuno­modu­la­tory agent – such as Revlimid, thalidomide (Thalomid), or Pomalyst (poma­lido­mide) – and who progressed within 60 days of completing their most recent regi­men (see related Beacon news).

Kyprolis belongs to the same class of drugs as Velcade, called proteasome inhibitors. As a single agent, Kyprolis has dem­onstrated efficacy and tolerability in re­lapsed and progressing myeloma patients. Further­more, it is not usually asso­ci­ated with the emergence of periph­eral neu­rop­athy (pain, tingling, or loss of sensation in the extremities due to nerve damage), a common Velcade-related side effect.

Results indicate that Kyprolis is also effective for newly diagnosed myeloma; however, the study Dr. Land­gren presented is the first to evaluate Kyprolis for smol­der­ing myeloma.  Kyprolis is not yet approved for use in either of these patient populations.

Study Design

The current Phase 2 study was designed to assess the efficacy of Kyprolis in com­bi­na­tion with Revlimid and low-dose dexa­meth­a­sone in high-risk smol­der­ing multiple myeloma patients.

The study was motivated, Dr. Landgren told The Beacon, by the positive results seen thus far when Kyprolis has been com­bined with Revlimid and dexa­meth­a­sone to treat newly diagnosed symp­tomatic myeloma patients.  Based in part on those results, the investigators felt it would be useful to see if they "could make significant delays and/or prevent multiple myeloma" by treating myeloma in its earlier, pre-symptomatic stages, Dr. Landgren explained.

The study investigators plan to recruit 12 high-risk smol­der­ing multiple myeloma patients.  So far, 10 patients with a median age of 55 years have been recruited.

Patients received 20 mg/m² of Kyprolis for the first two doses and then 36 mg/m² of Kyprolis on days 1, 2, 8, 9, 15, and 16 of up to eight 28-day treat­ment cycles.  Patients also received 25 mg of Revlimid on days 1 to 21, and 20 mg of dexa­meth­a­sone on days 1, 2, 8, 9, 15, 16, 22 and 23. The dexa­meth­a­sone dose was lowered to 10 mg per day after four treat­ment cycles.

Patients who achieved stable disease or better after all eight treat­ment cycles can con­tinue treat­ment with 10 mg of Revlimid on days 1 to 21 for an addi­tional 12 cycles.

Results

Thus far, patients have received a median of 5.5 treat­ment cycles.

At the time of the analysis, eight patients were evaluable for response. All of these patients responded to treat­ment, with 50 per­cent achieving a complete response or stringent complete response, 25 per­cent achieving a near complete response, 12.5 per­cent achieving a very good partial response, and 12.5 per­cent achieving a partial response.

Among the patients who achieved at least a near complete response, 80 per­cent did not show any signs of minimal residual disease based on a technique called flow cytometry.

According to Dr. Landgren, the response to treat­ment was rapid, with patients achieving a complete response within a median of 3.5 months.

The response rates seen in the study thus far are higher than those observed during the Spanish study testing only Revlimid and dexa­meth­a­sone in high-risk smol­der­ing myeloma patients.

In the Spanish study, 16 per­cent of the patients achieved a complete or stringent complete response after nine cycles of initial ther­apy.

In the current study, at a point where only 2 out of the 8 evaluable patients have completed all eight cycles of initial ther­apy, the com­bined complete and stringent complete response rate is already 50 per­cent.

Dr. Landgren pointed out that he and his colleagues observed limited severe side effects. The most com­mon severe side effects included low levels of lymphocytes (a type of white blood cell, 25 per­cent), rash (25 per­cent), elevated liver enzyme levels (12.5 per­cent), heart failure (12.5 per­cent), low red blood cell counts (12.5 per­cent), low platelet counts (12.5 per­cent), and low white blood cell counts (12.5 per­cent).

The one observed case of heart failure led to the patient's treat­ment being dis­con­tinued.  However, the patient had achieved a stringent complete response at that point, and has maintained it for three months since then.

There have been no cases thus far of patients experiencing either mild or severe periph­eral neu­rop­athy, Dr. Landgren told The Beacon.

Because the current study is still in its initial stages, it is too early to tell whether the three-drug com­bi­na­tion it is testing will have a survival impact equal to, or even greater, than was seen in the Spanish study.  Dr. Landgren told The Beacon that the greater complete response rate seen in the current study suggests the survival impact could be greater, but this will not be known for certain until more results from the current study become available.

Dr. Landgren also believes that, despite the positive data from both the Spanish trial and the current study, it is still to early to recommend active treat­ment of any smol­der­ing myeloma patients outside of clinical trials.

He explained to The Beacon that, "When the Spanish ran­domized Phase 3 study gets published, I am sure many doctors in the U.S. will consider using the same drug com­bi­na­tion [tested in that trial].  However, I think we would like to see a second study showing the same results before it becomes implemented more broadly."

For more in­­for­ma­tion, please see Dr. Landgren’s presentation slides, which he has made available for download and viewing as a courtesy to The Beacon’s readers.