The American Society of Clinical Oncology (ASCO) meeting in any given year is hit-or-miss as far as breaking research for multiple myeloma goes.

However, at ASCO 2015, there were no two views among myeloma experts. It was probably one of the most sig­nif­i­cant ASCO meetings as far as pre­senta­tions of abstracts that have the poten­tial to alter the land­scape of myeloma treat­ment in the near future.

There is no way to do justice to all the presentations at ASCO this year. However, I have tried to prepare a quiz to high­light the im­por­tant messages in a few of the pre­senta­tions that I thought were key.

1. The fol­low­ing are true about the ENDEAVOR trial except:
1. Kyprolis (car­filz­o­mib) 20/27 mg/m² and dexamethasone (Decadron) doubled pro­gres­sion-free survival com­pared with Velcade (bor­tez­o­mib) 1.3 mg/m² and dexa­meth­a­sone
2. The benefit of Kyprolis also was seen in patients who had prior exposure to Velcade
3. Kyprolis could be admin­istered for longer duration than Velcade
4. Kyprolis required fewer dose reductions due to adverse events

Correct answer: .

The ENDEAVOR trial was a Phase 3 comparison of the second generation pro­te­a­some inhibitor Kyprolis in com­bi­na­tion with dexa­meth­a­sone to Velcade and dexa­meth­a­sone. It dem­onstrated that Kyprolis at a dose of 56 mg/m² – which is higher than the 20/27 mg/m² dose cur­rently approved by Food and Drug Administra­tion (FDA) – resulted in a pro­gres­sion-free survival of 18.7 months com­pared with 9.4 months for Velcade (at the FDA-approved dose of 1.3 mg/m²) and dexa­meth­a­sone.

The benefit was seen both in patients who had prior exposure to Velcade (15.6 months versus 8.1 months) and in patients with no prior Velcade exposure (not reached versus 11.2 months). The benefit was also main­tained across age sub-groups: younger than 65 years (not reached versus 9.5 months), 65-74 years (15.6 months versus 9.5 months) and 75 years or older (18.7 months versus 8.9 months).

The median duration of treat­ment was 40 weeks for Kyprolis and dexa­meth­a­sone versus 27 weeks for Vel­cade and dexa­meth­a­sone. Just under a quarter (23 per­cent) of patients receiving Kyprolis and dexa­metha­sone required a dose reduction, com­pared with 47 per­cent of patients receiving Velcade and dexa­metha­sone.

Grade 2 or higher neu­rop­athy was observed in 6 per­cent of patients receiving Kyprolis com­pared with 32 per­cent for those receiving Velcade. Treatment with Kyprolis was asso­ci­ated with higher rates of hyper­ten­sion (25 per­cent versus 9 per­cent) and somewhat higher rates of cardiac failure (8 per­cent versus 3 per­cent).

For further in­­for­ma­tion about the results of the ENDEAVOR trial, see this ASCO meeting abstract.

2. Which of the fol­low­ing is true about the ELOQUENT-2 trial:
1. The trial showed that elotuzumab in com­bi­na­tion with Revlimid (lena­lido­mide) and dexa­meth­a­sone produced responses even in Revlimid-refractory patients
2. Elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone doubled the median pro­gres­sion-free survival com­pared to Revlimid and dexa­meth­a­sone alone
3. The pro­gres­sion-free survival dif­fer­ence noted at 1 year was main­tained after 2 years on ther­apy with elotuzumab, Revlimid and dexa­meth­a­sone
4. The benefit of elotuzumab in com­bi­na­tion with Revlimid and dexa­meth­a­sone is limited to a younger patient pop­u­la­tion

Correct answer: .

The ELOQUENT-2 trial was a Phase 3 trial comparison of elotuzumab (a mono­clonal anti­body to SLAM-F7) in com­bi­na­tion with Revlimid and dexa­meth­a­sone to Revlimid and dexa­meth­a­sone alone. The median pro­gres­sion-free survival was 19.4 months for elotuzumab, Revlimid, and dexa­meth­a­sone com­pared with 14.9 months with Revlimid and dexa­meth­a­sone.

The absolute pro­gres­sion-free survival dif­fer­ence at 1 and 2 years was 11 per­cent (68 per­cent versus 57 per­cent) and 14 per­cent (41 per­cent versus 27 per­cent). The hazard ratio was 0.70, which implies a 30 per­cent over­all reduction in risk for disease pro­gres­sion. This raises the possibility that a subset of patients may get a prolonged benefit from treat­ment with the drug, and this may not be fully captured by focusing on the median pro­gres­sion-free survival figures. Only longer follow-up will con­firm whether there truly is a “tail on the survival curve.”

The pro­gres­sion-free survival was superior in the elotuzumab arm both in patients under 65 years of age (25 per­cent reduction in risk for disease pro­gres­sion) and 65 years of age and older (35 per­cent reduction in risk for disease pro­gres­sion).

The trial, how­ever, excluded patients who were refractory to Revlimid in the past and, at this time, it is not known if the addi­tion of elotuzumab will prove effective in patients whose disease has progressed on Rev­limid alone.

Elotuzumab has been given breakthrough desig­na­tion by the FDA and this trial is ex­pec­ted to lead to the FDA approval of the elotuzumab within the next year.

For further in­­for­ma­tion about the results of the ELOQUENT-2 trial, see this ASCO meeting abstract, these presentation slides from the meeting (PDF; courtesy of Dr. Sagar Lonial), this related journal article, and this related Beacon news article.

3. Which of the fol­low­ing is true about the SIRIUS trial:
1. Daratumumab was effective as a single agent even in “quad” refractory patients
2. Daratumumab has no activity in patients with extramedullary disease
3. The median duration of response to dara­tu­mu­mab was 3.7 months
4. Daratumumab had a high rate dis­con­tinu­a­tion due to adverse events related to the fact that its target CD38 is ex­pressed on a variety of lymphoid and myeloid cells as well.

Correct answer: .

The SIRIUS trial was a Phase 2 study of single agent dara­tu­mu­mab (a mono­clonal anti­body to CD38) in pa­tients who had received 3 or more lines of prior ther­apy or were double refractory to a pro­te­a­some inhibitor and an immuno­modu­la­tory drug. Almost all patients enrolled (95 per­cent) were double refractory; 42 per­cent were refractory to Velcade, Revlimid, Kyprolis, Pomalyst (poma­lido­mide, Imnovid), and, in many cases, tha­lido­mide (Thalomid) as well.

The over­all response rate across all patients in the trial was 29 per­cent. Three per­cent of the patients achieved a stringent com­plete response (sCR), and 12 per­cent achieved a very good partial response (VGPR) – a remarkable feat for a single agent in this refractory a patient pop­u­la­tion. In addi­tion, it is notable that the single agent produced at least a partial response in 21 per­cent of patients who were “quad” refractory to Velcade, Revlimid, Kyprolis, and Pomalyst.

The SIRIUS study also showed that dara­tu­mu­mab had a response rate of 20 per­cent in patients with extra­medullary disease (which occurs when myeloma spreads to soft tissue structures beyond the confines of the bone marrow).

When con­sidering the entire study pop­u­la­tion (responders and non-responders), dara­tu­mu­mab produced a pro­gres­sion-free survival of 3.7 months. The duration of response, which limits the analysis to responding patients only, was 7.4 months.

The drug was well tolerated, with no dis­con­tinu­a­tions due to adverse events attributable to the drug. This is reassuring con­sidering the fact that the target for dara­tu­mu­mab is found on the surface of a variety of other cells in the bone marrow.

Daratumumab too has been granted breakthrough ther­apy desig­na­tion by the FDA, and this trial is ex­pec­ted to lead to the FDA approval of the drug within the next year.

For further in­­for­ma­tion about the results of the SIRIUS trial, see this ASCO meeting abstract, these pre­sen­ta­tion slides from the meeting (PDF; courtesy of Dr. Sagar Lonial), and this related Beacon news article.

4. Data presented at the ASCO 2015 meeting showed that CAR T cells directed at which of the fol­low­ing an­ti­gens could poten­tially have thera­peutic efficacy in patients with multiple myeloma:
1. B-cell membrane an­ti­gen (BCMA)
2. SLAMF7
3. CD138
4. CD19

Correct answer: .

T cells are naturally occurring immune cells deemed to have an im­por­tant role in the body’s surveillance against cancer cells. CAR T-cell ther­apy utilizes genetic engi­neer­ing techniques to modify these T cells to produce re­cep­tors that recog­nize proteins on specific cancer cells of interest. These re­cep­tors target the T cells to these particular cancer cells and help eradicate the cancer cells directly. In recent years CAR T cells targeted to CD19 (an an­ti­gen present on lymphoid cells) have shown robust efficacy in patients with a variety of lymphoid malig­nan­cies, in­clud­ing certain leukemias and lym­phomas.

Scientists have generated a variety of CAR T cells to an­ti­gens like BCMA, SLAMF7 and CD138 that are specific to myeloma cells. These are at various stages of pre-clinical and clin­i­cal devel­op­ment. At the ASCO 2015 meeting, the very first trial of CAR T cells in myeloma was reported. This trial utilized CD19-targeted CAR T cells. This trial enrolled patients who had re­lapsed within one year of a prior au­tol­o­gous stem cell trans­plant.  Patients received 10 million to 50 million CAR T-cells fol­low­ing a second au­tol­o­gous stem cell trans­plant.

Three out of five patients remained in remission with follow up ranging from 74 days to 339 days.  In two of these patients, the remission with the second trans­plant had exceeded the remission duration achieved fol­low­ing the first trans­plant.  One of these patients achieved MRD-negative com­plete remission and re­mained in remission with the longest follow up of 339 days.

CAR T cells do have sub­stan­tial toxicity due to release of chemical mediators of inflammation. However, progress is being made in ameliorating this toxicity. These results are fairly intriguing, especially since CD19 is not felt to be the best target for multiple myeloma. This further raises ex­pec­ta­tions for immuno­therapy to pay even greater dividends in the future using CAR-T cells that are more specific for myeloma cells.

For further in­­for­ma­tion about the results of the CAR T-cell trial results presented at the ASCO meeting, see this ASCO abstract and this related Beacon news article.

Dr. Ravi Vij is an asso­ci­ate pro­fessor of med­i­cine at the Washington University School of Medicine in St. Louis. Dr. Vij has clin­i­cal expertise in the man­agement of hema­to­logic malig­nan­cies and stem cell trans­plan­ta­tion. He has a special research interest in multiple myeloma and has been involved in de­vel­op­ment of novel ther­a­pies for the disease. He also works closely with basic science researchers engaged in cancer genomics to help translate the findings to the clin­i­cal man­agement of patients with myeloma.