One of the issues that a physician may consider when deciding how to treat a myeloma patient is the impact different treatment options may have on the pa­tient’s bones.

If a patient already has extensive bone damage resulting from multiple myelo­ma, a physician may lean more toward treatments that are believed to halt, or even counteract, the bone destruction the patient has been experiencing.

Previous research has shown that Velcade ^[1] (bortezomib) may be able to help rebuild the bones of myeloma patients (see related Beacon ^[2] news).

However, there is currently little data available on the effects of Revlimid ^[3] (lenalidomide) on myeloma bone disease.

Researchers from Greece therefore conducted two studies (one retrospective in nature, the other one pro­spective) to investigate the impact Revlimid has on the processes that lead to bone disease.

In both studies, Revlimid was administered together with dexamethasone ^[4] (Decadron), a standard com­bi­na­tion in multiple myeloma.  In one of the studies, some patients also were treated with Velcade in addition to the Revlimid and dexamethasone.

The results of both studies – which were published in a journal article earlier this year – were mixed.

In patients who responded to the two-drug regimen, it appeared to slow down the body's processes that lead to bone destruction.  It had no effect on bone destruction processes, however, in patients who did not respond to the treatment.

Moreover, regardless of response to the regimen, the Revlimid-dexamethasone combination did not show significant signs of encouraging the processes that lead to bone formation.

Patients who were treated with Velcade in addition to Revlimid and dexamethasone, however, had no­tice­ably different results, with clear signs of increased bone formation activity and reduced markers of bone destruction.

Based on these findings, the Greek researchers conclude that Revlimid plus dexamethasone is unlikely to be sufficient on its own to encourage bone regrowth in multiple myeloma patients.

The researchers point out, however, that their results support the administration of Velcade, Revlimid, and dexamethasone in relapsed and refractory multiple myeloma patients with extensive bone disease.

Background

The majority of myeloma patients have evidence of bone disease when they are first diagnosed with multiple myeloma, and bone disease is one of the most challenging complications of myeloma.

In multiple myeloma, bone disease occurs because of an imbalance between two competing activities in the bone.  While cells known as osteoblasts work to build up the tissue in the bone, other cells known as osteoclasts work to destroy bone tissue.

Myeloma patients typically receive treatment with drugs known as bisphosphonates, such as Zometa ^[5] (zoledronic acid) and Aredia ^[6] (pamidronate), to prevent the progression of bone disease.

In addition, some myeloma treatments, including Velcade, have been shown to have a positive effect on overall bone formation.

The combination of Revlimid plus dexamethasone, often referred to as RD, is commonly used to treat multiple myeloma.  The authors of the current study state, however, that the effect of this combination on bone disease is not well understood.  They therefore assessed how treatment with Revlimid plus dexamethasone affects the processes that lead to bone formation, and bone destruction, in relapsed and refractory myeloma patients.

Study Design

Investigators from Greece conducted two studies to investigate the effect of Revlimid plus dexamethasone on myeloma bone disease.

They first retrospectively analyzed the records of 106 relapsed and refractory multiple myeloma patients who received treatment with Revlimid plus dexamethasone. The median age of the patients was 68 years.

Patients had received a median of three prior therapies. The majority of the patients had previously received Velcade (61 percent) or thalidomide (72 percent).

The patients received 25 mg of Revlimid on days 1 to 21 plus 40 mg of dexamethasone on days 1 to 4 and 15 to 18 for the first four 28-day treatment cycles. Dexamethasone was administered only on days 1 to 4 of subsequent cycles.

The investigators also prospectively evaluated bone disease in 99 relapsed and refractory myeloma patients who were treated with either the same Revlimid plus dexamethasone regimen as in the retrospective study, or a regimen commonly referred to as VRD.  The VRD regimen consisted of 15 mg of Revlimid on days 1 to 14, 40 mg of dexamethasone on days 1 to 4, and 1 mg/m² of Velcade on days 1, 4, 8, and 11 of a 21-day treatment cycle.

The decision as to which patients in the prospective study received the two-drug versus the three-drug regimen was based on previous history of peripheral neuropathy.  Patients who in the past had experienced severe peripheral neuropathy (pain and tingling in the extremities due to nerve damage) received treatment with the Revlimid-dexamethasone combination instead of the three-drug regimen.

In addition, all patients received 4 mg of Zometa every 28 days as supportive treatment.

In both studies, the researchers used various markers to assess the impact of treatment on the bone build­ing and bone destruction processes going on in the patients' bodies.

One of the markers they measured was DKK1, which is a protein that inhibits the activity of osteoblasts, thereby slowing down the bone formation process. Myeloma patients have been known to have high levels of DKK1 (see related Beacon ^[7] news).

Another marker they looked at is known as CTX.  Higher levels of this marker indicate that higher levels of bone destruction are occurring in the body.

Study Results

Retrospective Study

Overall, 55 percent of patients in the retrospective study responded to Revlimid-dexametha­sone treat­ment, with 12 percent achieving a complete response, 11 percent a very good partial response, and 32 percent a partial response.

The investigators found that the levels of certain markers, including DKK1, were significantly associated with the presence of bone disease before treatment. For example, they noted that patients with more advanced bone disease had much higher levels of DKK1 compared to patients with little or no bone disease.

The investigators also found that DKK1 levels decreased, and levels of the bone degradation marker CTX slightly decreased, in patients who responded to treatment with RD.

Nevertheless, other markers that the investigators looked at did not show that the reduced levels of DKK1 in the patients who responded to the Revlimid-dexamethasone treatment actually led to increased bone for­ma­tion activity.

In addition, the markers tracked by the researchers indicate that the two-drug regimen did not slow bone destruction, or increase bone formation, in the patients who did not respond to the regimen.

The median progression-free survival across all patients in the retrospective study was 11 months, and the median overall survival was 18 months.

None of the markers for bone destruction or formation were associated with survival.

The most common side effects were low white blood cell counts (55 percent), fatigue (54 percent), low platelet counts (46 percent), and infections (32 percent).

Prospective Study

In the prospective study, the investigators found that the overall response rates were similar among patients who received RD (61 percent) and those who received VRD (63 percent).

Furthermore, the time to best response was also similar between the two groups (1.6 months versus 2.2 months, respectively).

However, the investigators found that VRD was more effective than RD in suppressing bone destruction and enhancing bone formation

In patients treated with RD who did not respond to the regimen, neither the bone formation nor bone de­struc­tion processes seemed to be affected by the two-drug regimen.

Among the patients who responded to RD, there was actually a slight increase in DKK1, the protein that in­hibits bone formation.  However, there was also a significant reduction in the CTX marker in these patients, indicating that the treatment successfully slowed down the bone destruction process in the patients.

The results for the patients who were treated with the VRD regimen were markedly different.

In those patients, there were consistent signs across the various markers that the treatment regimen led to both increased bone formation activity and to decreased bone destruction activity.  This was true whether or not patients responded to the three-drug regimen.

Across all patients treated with the VRD regimen, the treatment "dramatically" reduced levels of the bone formation inhibitor DKK1, the authors note, and did the same for the CTX marker of bone destruction activity

Nevertheless, the median progression-free survival was similar between RD patients (9 months) and VRD patients (7 months). In addition, the median overall survival was the same for patients receiving RD and those who received VRD (16 months).

For more information, please refer to the study in the American Journal of Hematology ^[8] (full text).