During the upcoming annual meeting of the American Society of Clinical Oncology (ASCO), results will be presented from clin­i­cal trials involving poten­tial new drugs under devel­op­ment for the treat­ment of multiple myeloma.

In particular, results for newer, lesser known agents that are in the early stages of clin­i­cal devel­op­ment will take center stage. These agents in­clude obatoclax ^[1], siltuximab ^[2], daratumumab ^[3], and SNS01-T ^[4].

According to the recently released ASCO abstracts, the agents showed varying degrees of activity in re­lapsed and refractory myeloma patients. So it will be particularly in­ter­est­ing to see and hear how the myeloma experts react to the initial findings for these com­pounds.

The current article summarizes the pre­lim­i­nary results from these agents, based on the data avail­able in the meeting abstracts.

Obatoclax

Obatoclax is being devel­oped by the pharma­ceu­tical com­pany Cephalon, a sub­sid­i­ary of Teva Pharma­ceu­ticals (NASDAQ: TEVA). It is an inhibitor of the Bcl-2 family of proteins. This inhibition causes cell death in cancer cells, preventing tumor growth. Obatoclax is cur­rently being in­ves­ti­gated as a treat­ment for solid tumors as well as for a variety of blood cancers, in­clud­ing multiple myeloma, leukemia, and lym­phoma.

At ASCO, Dr. A. K. Stewart from the Mayo Clinic in Arizona will discuss results of a Phase 1 study of obatoclax in com­bi­na­tion with Velcade ^[15] (bor­tez­o­mib) for the treat­ment of re­lapsed multiple myeloma.

Since it is a Phase 1 trial, the study pop­u­la­tion is small. The abstract con­tains data from 11 patients. The median patient age was 62 years. The median time from diag­nosis was 4.7 years.

Patients received a starting dose of 14 mg/m² of obatoclax as a 24-hour con­tin­uous in­fusion on days 1, 8, and 15 of a 21-day treat­ment cycle, which was then amended to either 30 mg/m² or 40 mg/m² of obatoclax as a three-hour con­tin­uous in­fusion on days 1, 8, and 15. In addi­tion, patients received 1.3 mg/m² of Velcade on days 1, 4, 8, and 11.

Ten patients were evaluable for response; 40 per­cent of patients achieved a partial response and 10 per­cent achieved a minor response. None of the patients who received 40 mg/m² of obatoclax as a three-hour con­tin­uous in­fusion responded.

The researchers did not observe any dose-limiting side effects at the 30 mg/m² dose level, so it was de­ter­mined to be the maximum tolerated dose.

The most commonly observed side effects were blood-related or neurologic in nature.

Siltuximab

Siltuximab is a com­pound that blocks the activity of IL-6, a protein that facilitates myeloma cell growth and resistance to dexamethasone ^[16] (Decadron). It is being devel­oped by Janssen Biotech, a Johnson & Johnson com­pany (NYSE: JNJ), and has been in­ves­ti­gated for the treat­ment of prostate cancer, ovarian cancer, metastatic renal cell cancer, and Castleman’s disease (excessive growth of lymphatic cells).

At ASCO, Dr. Robert Orlowski from the MD Anderson Cancer Center in Houston will present results from a Phase 2 study com­par­ing siltuximab plus Velcade to Velcade alone in re­lapsed and refractory myeloma patients.

The study in­cluded 286 patients who received either 6 mg/kg of in­tra­venous siltuximab twice weekly plus 1.3 mg/m² of Velcade on days 1, 4, 8, 11, 22, 25, 29, and 32 in a 42-day treat­ment cycle or Velcade alone for a maximum of four treat­ment cycles. After that, Velcade was reduced to once weekly in 35-day treat­ment cycles.

Patients who progressed dis­con­tinued Velcade and could receive 40 mg of dexa­meth­a­sone daily on days 1 through 4, 9 through 12, and 17 through 20 of a 28-day treat­ment cycle for a maximum of four cycles. In sub­se­quent treat­ment cycles, dexa­meth­a­sone was admin­istered on days 1 through 4 until disease pro­gres­sion.

Patients who received siltuximab plus Velcade were slightly older (median age 64 years) than patients receiving Velcade alone (61 years).

The median treat­ment duration was five months in both treat­ment groups, and the median follow-up time was 24.5 months.

More patients on siltuximab plus Velcade responded to treat­ment (55 per­cent) than patients on Velcade alone (47 per­cent). Complete response rates were 11 per­cent for patients receiving siltuximab plus Velcade and 7 per­cent for patients receiving Velcade alone.

The median pro­gres­sion-free survival time was longer for patients receiving siltuximab plus Velcade (8.1 months), com­pared to patients receiving Velcade alone (7.6 months).

However, the median over­all survival was longer for patients receiving Velcade alone (36.9 months), com­pared to those receiving siltuximab plus Velcade (30.8 months).

More patients receiving siltuximab plus Velcade ex­peri­enced severe or life-threatening side effects (91 per­cent) than patients receiving Velcade alone (74 per­cent).

Daratumumab

Daratumumab is being devel­oped by the Danish pharma­ceu­tical com­pany Genmab.  It is a mono­clonal anti­body that binds to the CD38 molecule, which is found on the surface of multiple myeloma cells.  Dara­tu­mu­mab then signals for the immune sys­tem to kill the myeloma cells.

At ASCO, Dr Torben Plesner from Vejle Hospital in Vejle, Denmark, will present pre­lim­i­nary efficacy results from a Phase 1/2 study of dara­tu­mu­mab in re­lapsed and refractory myeloma patients.

Study par­tic­i­pants received escalating doses of dara­tu­mu­mab ranging from 0.005 mg/kg to 24 mg/kg.

The data in­cluded in the abstract is based on data from 23 patients who received up to 4 mg/kg of dara­tu­mu­mab.

Daratumumab’s pre­lim­i­nary efficacy evaluation is based on the change in mono­clonal (M) protein in the blood or urine.

Of the patients receiving up to 1 mg/kg of dara­tu­mu­mab, 18 per­cent of patients achieved a reduction in M-protein ranging from 12 per­cent to 19 per­cent. Of the patients receiving 2 mg/kg, a third achieved a reduction in M-protein of 55 per­cent. In the 4 mg/kg group, all patients achieved a reduction in the M-protein ranging from 49 per­cent to 64 per­cent.

In addi­tion, all patients in the 4 mg/kg group showed a marked reduction in the per­cent­age of plasma cells in the bone marrow ranging from 80 per­cent to 97 per­cent.

According to the researchers, the drug’s side effects at these doses are man­ageable.

SNS01-T

SNS01-T is being devel­oped by the pharma­ceu­tical com­pany Senesco (NYSEAMEX: SNT). It selectively causes cells to die by targeting a protein called eIF5A, which is believed to be an im­por­tant regulator of cell growth and cell death.  SNS01-T is a nanoparticle that has three components: the first part targets myeloma cells with the natural form of eIF5A; the second part causes the cells to create an ineffective version of eIF5A; and the third part is a polymer that is used to deliver the complex to the myeloma cells.

During a poster session on Monday, June 4, results will be presented from a Phase 1/2 trial investigating the safety and tolerability of SNS01-T in re­lapsed and refractory multiple myeloma patients.

The abstract cur­rently does not in­clude any study results. Dr. John Lust from the Mayo Clinic, the study’s lead investigator, stated to The Myeloma Beacon in request for further in­for­ma­tion that the study is a 'trial in progress' and that he cannot provide more in­for­ma­tion at this time than what is in­cluded in the abstract.

For more in­for­ma­tion, please see abstracts 8013 ^[17] (obatoclax), 8018 ^[18] (siltuximab), 8019 ^[19] (dara­tu­mu­mab), and TPS8116 ^[20] (SNS01-T) on the ASCO ^[21] meeting website.