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Constellation Pharmaceuticals recently initiated a Phase 1 clinical trial that will test whether single-agent CPI-0610 is safe and effective as an anti-myeloma therapy.

The clinical trial is taking place at a several locations across the United States, and is open to multiple myeloma patients who have relapsed after at least one previous myeloma treatment regimen.

CPI-0610 is a small molecule that inhibits bromodomain and extra-terminal (BET) proteins, which are involved in regulating the cell cycle and cell death. Bromodomain inhibitors, which include the compound JQ1, have attracted attention in recent years as potential treatments for a range of different cancers, including multiple myeloma.

A Phase 1 clinical trial of CPI-0610 as a potential treatment for lymphoma has been ongoing since last summer. The Phase 1 trial in myeloma and another Phase 1 trial in patients with acute leukemias and myelodysplastic syndromes have been added based on preclinical research showing blood-related cancers may be highly sensitive to BET inhibition.

For more information about the trial, see the trial description at the U.S. clinical trial registry.

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Siltuximab, a drug that has been tested as a potential new treatment for multiple myeloma, was approved last week by the U.S. Food and Drug Administration (FDA).

Its approval, however, was as a new treatment for a form of Castleman's dis­ease, a rare disorder similar to lymphoma.

Siltuximab will be marketed in the United States by the Janssen Biotech division of Johnson & Johnson (NYSE:JNJ).  The drug's brand name will be Sylvant.

Johnson & Johnson also has submitted an application with the European Medi­cines Agency to market siltuximab in Europe as a treatment for Castleman's disease. A decision on the Euro­pe­an application, however, has not yet been announced.

Siltuximab has been investigated in several clinical trials as a potential treatment for myeloma.  Initial results for one trial were presented at the American Society of Hematology annual meeting in 2011.  The results showed that siltuximab was active against multiple myeloma, but patients treated with the drug also ex­peri­enced significant side effects (see related Beacon news article).   Updated results from that trial were pub­lished last year, and another study was published recently examining the impact of siltuximab on the heart function of myeloma patients treated with the drug.

Only one clinical trial of siltuximab in myeloma patients is still ongoing and recruiting patients.  The inter­na­tion­al multicenter trial is testing siltuximab as a potential treatment for high-risk smoldering myeloma.

It's not known whether the location of Janssen Biotech's headquarters – which is in Pennsylvania – influ­enced the company's decision to select Sylvant as the brand name for sil­tuximab.

For more information about siltuximab's FDA approval, see the related press releases from the FDA and Johnson & Johnson.

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Celgene Submits Revlimid For Approval As First-Line Therapy – The phar­ma­ceut­i­cal company Celgene has announced that it has filed applications with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) seeking official approval of Revlimid (lenalidomide) as a treatment for newly diagnosed multiple myeloma. The application with the FDA was filed in April, while the EMA application was filed in February.  Analysts expect the agen­cies to reach decisions on the applications by the middle of next year. Revlimid currently has regulatory approval in the U.S. and Europe for use in relapsed and refractory myeloma. However, Revlimid – alone or in combination with other anti-myeloma agents – is often used for the treatment of newly diagnosed patients in the United States, where such “off-label” prescribing is legally permitted. Because off-label prescribing is less com­mon outside the U.S., a positive EMA decision in regard to the Revlimid application could signif­i­cant­ly ex­pand the drug's use in Europe. For more information, please see the Celgene press release re­gard­ing its 2014 first quarter earnings.

U.K. Agency Approves Velcade For Newly Diagnosed Myeloma – The National Institute for Health and Clinical Excellence (NICE), the agency that sets treatment guidelines for the U.K.'s National Health Service in England and Wales, earlier this week approved the use of Velcade (bortezomib) in newly diagnosed multiple myeloma patients eligible for stem cell transplantation. The decision specifies that Velcade is to be given in combination with dexamethasone (Decadron) or with dexamethasone and thalidomide (Thalomid). This week's NICE decision supplements a 2011 decision regarding the use of Velcade in newly diag­nosed patients ineligible for transplantation. For those patients, however, NICE has approved the use of Velcade only if a patient cannot tolerate treatment with thalidomide (see related Beacon news). For more in­for­ma­tion, see the NICE press release.

New Formulation Of IV Melphalan Meets Primary Endpoint In Key Phase 2 Trial – The pharmaceutical company Spectrum Pharmaceuticals announced earlier this week that its Phase 2 pivotal trial of a new formulation of intravenous melphalan (Alkeran) met its primary endpoint. Given the results of the trial, the company is expected to file an application with the FDA during the third quarter of this year requesting per­mission to market the drug in the United States.  The new formulation of melphalan, which Spectrum calls "Captisol-enabled melphalan", does not include propylene glycol, a chemical that has been reported to have heart- and kidney-related side effects.  The Captisol technology also improves the stability of Spec­trum's melphalan formulation.  Together, the improved stability and lack of propylene glycol may allow Spec­trum's formulation to be administered at doses higher than can be safely achieved with currently available mel­pha­lan formulations.  Captisol technology also is used in the formulation of Kyprolis (car­filz­o­mib).  The primary endpoint in the pivotal Phase 2 trial of propylene gylcol-free melphalan was overall safety.  The drug was tested at a dose of 200 mg/m² in myeloma patients undergoing autologous (own) stem cell trans­plan­ta­tion. Currently available formulations of melphalan also are typically dosed at 200 mg/m² dose when they are used during the stem cell transplant process.  For more information, please see the Spec­trum Pharma­ceut­i­cals press release.

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Findings from a recent retrospective study conducted in Korea indicate that a combination of dex­a­meth­a­sone, cyclo­phos­phamide, etoposide, and cisplatin may be a suitable bridging therapy for relapsed multiple myeloma patients who previously received treatment with novel agents.

Most patients responded to the combination as salvage therapy or achieved stable disease, but the response rates were not durable.  Therefore, the researchers suggested that the combination might serve better as bridging therapy - to stabilize the myeloma until the patients receive further treatment, such as stem cell transplantation or access to investigational therapies in clinical trials.

These results are particularly relevant for multiple myeloma patients in countries where access to novel agents, such as thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide), is restricted, and also patients for whom novel agents no longer work.

The retrospective analysis was based on data from 59 patients who received dexa­metha­sone (Decadron), cyclo­phos­pha­mide (Cytoxan), etoposide (VP-16), and cisplatin, commonly referred to as DCEP, as salvage therapy between 2006 and 2013. The median patient age was 58 years, and patients had received a median of three prior therapies, including at least one novel agent such as thalidomide, Revlimid, or Velcade.

Overall, 45 percent of patients responded to the treatment, with 2 percent achieving a complete response, 2 percent a very good partial response, and 41 percent a partial response. An additional 16 percent of patients achieved a minor response and 20 percent had stable disease.

The median progression-free survival was 3.7 months and the median overall survival was 8 months, which according to the researchers indicate that a durable response is hard to achieve with this regimen. Based on these findings, the researchers conclude that DCEP may be more suitable as a bridging therapy by stabilizing the disease for the next treatment.

The most common severe side effects were blood-related and included low white blood cell counts (92 percent), low platelet counts (76 percent), and low red blood cell counts (71 percent).  Overall, 62 percent of patients discontinued treatment due to side effects.

The treatment-related death rate was notable at 15 percent.  Nearly all of the treatment-related deaths were due to infection in patients with low white blood cell counts.  

The researchers therefore recommend that patients being treated with DCEP also receive growth factors to increase blood cell counts and reduce the chance of infection.

For more information, please refer to the study in the Annals of Hematology (abstract).

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Results from a small retrospective analysis conducted in Japan indicate that injection site reactions from subcutaneous (under the skin) injections of Velcade (bor­tezo­mib) are more likely to occur during the first cycle of treatment than in later cycles.

A third of patients in the study developed injection site re­ac­tions – such as swell­ing, redness, or itchi­ness – during the first cycle of treatment.  However, the share of patients experiencing such reactions dropped to one fifth during later cycles.

In the Japanese study, investigators retrospectively analyzed data from 20 multiple myeloma patients with a median age of 72 years who were newly diagnosed (60 percent) or had relapsed/refractory disease (40 percent).

Overall, 65 percent of patients developed injection site reactions at some point during their subcutaneous Velcade treatment.

The Japanese researchers found that the rate of injection site reactions was significantly higher during the first treatment cycle compared to subsequent cycles (34 percent versus 20 percent, respectively).

The rate of moderate or severe injection site reactions was also significantly higher during the first cycle compared to subsequent cycles (16 percent versus 1 percent, respectively).

Injections in the abdomen caused fewer moderate or severe injection site reactions (2 percent), compared to injections in the thigh (11 percent).

According to the researchers, the higher rates seen with injections to the thigh may be due to the fact that the thigh contains less fat tissue than the abdomen.

The researchers note that stage of disease and patient weight had no impact on the rate or severity of the injection site reactions.

Based on their findings, they recommend better management of injection site reactions, particularly among patients who receive injections in their thigh during their first treatment cycle.

They add that treatment with corticosteroids may prevent, or provide relief from, injection site reactions.

For more information, please refer to the study in the International Journal of Hematology (abstract).

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In a recent study conducted in Korea, investigators found that myeloma patients who had higher weights at diagnosis had the longest survival.

Patients who were underweight at diagnosis, on the other hand, had the lowest survival.

The results of the Korean study are similar to those reported by a recent study that examined weight at diagnosis and its impact on survival in U.S. veterans diagnosed with myeloma (see related Beacon news).

In the Korean study, investigators retrospectively analyzed data for 193 myeloma patients who were diag­nosed from 1998 to 2012 at a single treatment center.  For each patient, the researchers had data that al­lowed them to calculate the patient's body mass index (BMI) at the time of diagnosis.

BMI is a measure of how overweight, or underweight, a person is.  It is calculated based on a person’s height and weight.

The researchers divided the patients in the study into three groups based on their BMI at diagnosis.  The first group was patients who were underweight (BMI below 20 kg/m²).  The second group was patients who had a healthy weight (BMI of 20 kg/m² to 24.9 kg/m²).  The third group was patients who were overweight (BMI of 25 kg/m² or above).

Median survival for the patients in the three groups increased as weight at diagnosis increased.

In particular, median survival was 26 months for patients who were underweight, 57 months for patients with a healthy weight, and 76 months for patients who were overweight at diagnosis.

The researchers also found that patients in the study who were underweight at the time of diagnosis had lower hemoglobin levels, higher calcium levels in their blood, and higher rates of kidney failure at diagnosis than the patients in the other two weight categories.

However, even when the researchers controlled for factors such as patient age, disease stage, type of initial treatment, and response to initial treatment, they still found that being underweight at diagnosis had a sta­tis­ti­cal­ly significant negative impact on a patient's likelihood of survival.

For more information, please refer to the study in the Annals of Hematology (abstract).

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Researchers from the U.S. National Cancer Institute recently initiated a Phase 1 clin­i­cal trial that will test whether dinaciclib in combination with Velcade and dexa­meth­a­sone is safe and effective as an anti-myeloma therapy.

The clinical trial is taking place at a several locations across the United States, and is open to multiple myeloma patients who have relapsed after at least one previous myeloma treatment regimen.

Dinaciclib (SCH727965) is currently being developed by Merck (NYSE: MRK). It is a small molecule that inhibits enzymes called cyclin-dependent kinases, which regulate the cell cycle and are often overactive in cancer cells. Dinaciclib interrupts the cell cycle by inhibiting these kinases, ultimately causing the cell to die.

Preclinical studies have shown that Velcade (bortezomib) is more effective when cyclin-dependent kinases are inhibited, and a previous Phase 1/2 study showed that dinaciclib is safe and active as a monotherapy for relapsed/refractory myeloma (see related Beacon news).

Therefore, this study is being conducted to determine the efficacy and safety of dinaciclib in combination with Velcade and dexamethasone (Decadron).

For more information about the trial, see the trial description at the U.S. clinical trial registry.