What a year 2015 was for the myelomatologist!

The U.S. Food and Drug Admin­istra­tion (FDA) ap­prov­al of three new myeloma drugs, all within the span of a few weeks to­wards the end of the year, had already gen­er­ated great ex­cite­ment in the com­munity.

Then, sev­er­al poten­tial prac­tice-changing pre­sen­ta­tions at the 2015 American Society of He­ma­tol­ogy (ASH) annual meeting put the proverbial icing on the cake to round out a landmark year for myeloma thera­peutics.

This edition of the myeloma quiz highlights some of the key takeaways from the ASH 2015 meeting.

1. All the fol­low­ing state­ments are true re­gard­ing data from ran­domized trials pre­sented at the meeting except:
1. Velcade, Revlimid and dexa­meth­a­sone im­proved pro­gres­sion-free sur­vival com­pared with Revlimid and dexa­meth­a­sone for patients with newly diag­nosed mul­ti­ple myeloma
2. Velcade, Revlimid, and dexa­meth­a­sone im­proved over­all sur­vival com­pared with Revlimid and dexa­meth­a­sone for patients with newly diag­nosed mul­ti­ple myeloma
3. Ninlaro (ix­az­o­mib), Revlimid, and dexa­meth­a­sone im­proved pro­gres­sion-free sur­vival com­pared with Revlimid and dexa­meth­a­sone for patients with re­lapsed/refractory mul­ti­ple myeloma
4. Ninlaro, Revlimid, and dexa­meth­a­sone im­proved over­all sur­vival com­pared with Revlimid and dexa­meth­a­sone for patients with re­lapsed/refractory mul­ti­ple myeloma.

Correct answer:

The ran­domized Phase 3 S0777 trial com­pared the three-drug com­bi­na­tion of Velcade (bor­tez­o­mib), Revlimid (lena­lido­mide), and dexamethasone (VRd) to Revlimid and dexa­meth­a­sone (Rd) in patients with pre­vi­ously untreated mul­ti­ple myeloma without an intent for im­medi­ate au­tol­o­gous stem cell trans­plant (abstract 25).

After a median follow-up of 55 months, the over­all re­sponse rate was 81.5 per­cent for VRd versus 71.5 per­cent for Rd, with com­plete remission rates of 15.7 per­cent and 8.4 per­cent, re­spec­tively. The median pro­gres­sion-free sur­vival was 43 months for VRd and 13 months for Rd (p= 0.0018). The over­all sur­vival also favored the VRd arm, 75 months versus 64 months for Rd (p= 0.0025).

Ninlaro is an orally admin­istered ther­apy in the same family of treat­ments – known as pro­te­a­some in­hib­i­tors – as Velcade and Kyprolis (car­filz­o­mib). Ninlaro recently was approved by the FDA for the treat­ment of mul­ti­ple myeloma (see re­lated Beacon news). Its ap­prov­al was based on the ran­domized Phase 3 TOURMALINE-MM1 study com­par­ing treat­ment with Ninlaro in com­bi­na­tion with Revlimid and dexa­meth­a­sone (IRd) to Rd alone. The re­­sults of the trial were pre­sented at the 2015 ASH meeting (abstract 727).

Patients participating in the trial could have re­ceived one to three prior treat­ments. Patients re­frac­tory to pre­vi­ous pro­te­a­some in­hib­i­tor-based or Revlimid-based treat­ment were excluded from the study. Progression-free sur­vival was superior in the IRd arm com­pared to the Rd arm (20.6 months versus 14.7 months, p=0.012). Over­all re­sponse rates (78.3 per­cent versus 71.5 per­cent, p=0.035) and com­plete re­sponse rates (11.7 per­cent versus 6.6 per­cent, p=0.019) also favored the three-drug arm. The median over­all sur­vival was not reached in either arm.

2. Which of the fol­low­ing is true about the re­­sults from the Intergroupe Francophone du Myeloma (IFM) 2009 trial?
1. Velcade, Revlimid, and dexa­meth­a­sone followed by au­tol­o­gous stem cell trans­plan­ta­tion re­­sulted in superior pro­gres­sion-free sur­vival com­pared with the use of Velcade, Revlimid, and dexa­meth­a­sone alone
2. Velcade, Revlimid, and dexa­meth­a­sone followed by au­tol­o­gous stem cell trans­plan­ta­tion re­­sulted in superior over­all sur­vival com­pared with the use of Velcade, Revlimid, and dexa­meth­a­sone alone
3. Velcade, Revlimid, and dexa­meth­a­sone followed by au­tol­o­gous stem cell trans­plan­ta­tion re­­sulted in similar minimal residual dis­ease negativity rates com­pared with the use of Velcade, Revlimid, and dexa­meth­a­sone alone.
4. A neg­a­tive PET-CT scan pre-maintenance predicted for superior pro­gres­sion-free sur­vival, but not over­all sur­vival, in the au­tol­o­gous trans­plant arm of the study.

Correct answer:

In the Intergroupe Francophone du Myeloma (IFM) 2009 trial, patients were assigned to one of two treat­ment arms (abstract 391). On the con­ven­tional ther­apy arm, patients re­ceived eight cycles of treat­ment with VRd. After three cycles of VRd, patients on this arm underwent stem cell mobilization with high-dose cyclo­phos­phamide (Cytoxan) and a granulocyte colony stim­u­lating factor such as Neupogen (filgrastim). On the trans­plant arm, patients re­ceived three cycles of VRd followed by stem cell collection and then au­tol­o­gous stem cell trans­plan­ta­tion with mel­phalan 200 mg/m² used for con­di­tioning. This was followed by two cycles of VRd as con­sol­i­da­tion. Maintenance treat­ment consisted of Revlimid 10 to 15 mg/day and was given to patients in both arms for one year.

A total of 764 patients were en­rolled and 700 were ran­domized. After a median follow-up of 39 months, the in­de­pen­dent data monitoring com­mit­tee rec­om­mended the trial be stopped on account of the superior re­­sults noted for patients on the trans­plant arm. The com­plete re­sponse, very good partial re­sponse, and partial re­sponse rates on the trans­plant and VRd arms were 59, 29, 11 per­cent, and 49, 29, and 20 per­cent, re­spec­tively (p=0.02). Among patients on the trans­plant arm, 88 per­cent achieved at least a very good partial re­sponse, com­pared to 78 per­cent on the VRd arm (p=0.001). The median pro­gres­sion-free sur­vival was 43 months for the trans­plant arm and 34 months for the VRd arm (p<0.001).

As patients in the con­ven­tional ther­apy arm of the study are allowed to get a trans­plant at time of dis­ease pro­gres­sion, this trial is unlikely to answer the question of whether ad­vances in con­ven­tional ther­apy allow for similar over­all sur­vival in the absence of stem cell trans­plan­ta­tion. However, no data was pre­sented on the rates of salvage trans­plan­ta­tion in the con­ven­tional ther­apy arm. The authors concluded that, in an era of new drugs, trans­plan­ta­tion should remain a standard of care.

Eighty per­cent of patients on the trans­plant arm achieved minimal residual dis­ease (MRD) negativity by flow cytometry com­pared to 65 per­cent on the VRd arm (p=0.001). A neg­a­tive PET-CT scan pre-maintenance predicted for both superior pro­gres­sion-free sur­vival and superior over­all sur­vival in the au­tol­o­gous trans­plant arm of the study (abstract 395).

3. Which of the fol­low­ing is true about data on mono­clonal anti­bodies for the treat­ment of mul­ti­ple myeloma?
1. Updated re­­sults from the Phase 3 study of Empliciti (elo­tuzu­mab), Revlimid, and dexa­meth­a­sone showed statistically superior over­all sur­vival com­pared to Revlimid and dexa­meth­a­sone
2. Updated re­­sults from the Phase 3 study of Empliciti, Velcade, and dexa­meth­a­sone showed statistically superior pro­gres­sion-free sur­vival com­pared to Velcade and dexa­meth­a­sone
3. Darzalex (dara­tu­mu­mab) when com­bined with Revlimid and dexa­meth­a­sone was asso­ci­ated with much higher rates of in­fusion reac­tions than Darzalex admin­istered alone
4. Darzalex when com­bined with Pomalyst and dexa­meth­a­sone pro­duced re­sponses in more than two-thirds of patients dual re­frac­tory to a pro­te­a­some in­hib­i­tor and an immuno­modu­latory drug such as Revlimid or thalido­mide.

Correct answer:

Empliciti, a mono­clonal anti­body to SLAMF7, was recently approved by the FDA (see re­lated Beacon news). Its ap­prov­al was based on re­­sults of the ELOQUENT-2 trial, a Phase 3 ran­domized open label study of Empliciti in com­bi­na­tion with Revlimid and dexa­meth­a­sone (ERd) in patients with re­lapsed re­frac­tory mul­ti­ple myeloma. The re­­sults of this trial were first pre­sented at the ASCO 2015 meeting (see re­lated Beacon news).

At the ASH meeting, up­dated data provided longer follow-up re­­sults (abstract 28, re­lated presentation slides). Previously, 1-year pro­gres­sion-free sur­vival figures were 68 per­cent versus 57 per­cent, and 2-year pro­gres­sion-free sur­vival figures 41 per­cent versus 27 per­cent, in favor of the three-drug com­bi­na­tion of ERd com­pared with Rd alone. In the ASH up­date, the 3-year pro­gres­sion-free sur­vival was 26 per­cent and 18 per­cent in the two arms, re­spec­tively. A time-to-next-treatment analysis favored the Empliciti arm (33 months versus 23 months). Interim over­all sur­vival analysis dem­onstrated a trend in favor of ERd, but this was not statistically sig­nif­i­cant (43.7 months versus 39.6 months, p=0.0257).

Also at the ASH meeting, two-year follow-up data were pre­sented from the Phase 2 ran­domized study of Empliciti plus Velcade and dexa­meth­a­sone versus Velcade and dexa­meth­a­sone trial (abstract 510). This trial en­rolled a total of 152 patients.

The median pro­gres­sion-free sur­vival in the Empliciti, Velcade, and dexa­meth­a­sone arm of the study was 9.9 months versus 6.8 months in the Velcade and dexa­meth­a­sone arm. The two-year follow-up showed a 24 per­cent re­duc­tion in the risk of dis­ease pro­gres­sion, and over­all sur­vival analysis showed a 25 per­cent re­duc­tion in the risk of death. An in­ter­est­ing observation was that patients with the V/V form of the FCGR3A gene had better out­comes when treated with Empliciti, Velcade, and dexa­meth­a­sone than those with the F/F form of the gene. However, being a Phase 2 study, the trial was not powered to assess the true ben­e­fit of Empliciti, Velcade, and dexa­meth­a­sone com­pared with Velcade and dexa­meth­a­sone alone.

Darzalex, a mono­clonal anti­body to CD38, was recently approved by the FDA for use as mono­therapy in mul­ti­ple myeloma patients who have re­ceived at least three prior lines of ther­apy (see re­lated Beacon news). At the ASH 2015 meeting, re­searchers reported re­­sults of a Phase 1/2 study (GEN503) of Darzalex in com­bi­na­tion with Revlimid and dexa­meth­a­sone in patients who had re­lapsed or re­lapsed and re­frac­tory mul­ti­ple myeloma (abstract 507, re­lated presentation slides).

The GEN503 study en­rolled 32 patients; 72 per­cent of the patients had prior exposure to an immuno­modu­la­tory drug (Revlimid in 34 per­cent of the patients, and thalidomide in 44 per­cent), and 91 per­cent of the study par­tic­i­pants had prior exposure to a pro­te­a­some in­hib­i­tor.

After a median follow-up of 15.6 months, the over­all re­sponse rate was 81 per­cent, in­clud­ing 28 per­cent with a very good partial re­sponse and 34 per­cent with either a com­plete or stringent com­plete re­sponse. The pro­gres­sion-free sur­vival was 72 per­cent at 18 months and over­all sur­vival 90 per­cent at 18 months. The type and rate of in­fusion-related reac­tions were similar to those reported in stud­ies of Darzalex mono­therapy.

Another open label, multi­center study of Darzalex in­ves­ti­gated the drug in com­bi­na­tion with Pomalyst (poma­lidomide, Imnovid) and dexa­meth­a­sone in re­lapsed or re­lapsed and re­frac­tory mul­ti­ple myeloma patients with at least two lines of prior ther­apy (abstract 508). A total of 98 patients, with a median of four prior lines of ther­apy, en­rolled in the Phase 1b trial; 66 per­cent of patients were re­frac­tory to Velcade, 30 per­cent re­frac­tory to Kyprolis, 69 per­cent re­frac­tory to Revlimid, and 67 per­cent were dual re­frac­tory.

The over­all re­sponse rate was 71 per­cent, in­clud­ing a 67 per­cent re­sponse rate in double re­frac­tory patients. After a median follow-up of 4.2 months, the six-month esti­mated pro­gres­sion-free sur­vival was 66 per­cent. No addi­tional safety signals were observed.

4. Which of the fol­low­ing is true about data on novel im­mune-oncology ap­proaches for patients with mul­ti­ple myeloma?
1. Keytruda (pem­bro­lizu­mab) in com­bi­na­tion with Revlimid and dexa­meth­a­sone pro­duced re­sponses even in patients with dis­ease re­frac­tory to Revlimid and dexa­meth­a­sone
2. Keytruda in com­bi­na­tion with Pomalyst and dexa­meth­a­sone pro­duced re­sponses even in patients with dis­ease re­frac­tory to Pomalyst and dexa­meth­a­sone
3. Fludarabine and cyclo­phos­pha­mide followed by CD19 CAR T cells has shown robust re­sponses in patients with re­lapsed/refractory mul­ti­ple myeloma
4. Autologous stem cell trans­plan­ta­tion followed by BCMA CAR T cells has shown robust re­sponses in patients with re­lapsed/refractory mul­ti­ple myeloma.

Correct answer:

Immuno-oncology, the use of drugs that target the im­mune sys­tem of the patient to eradicate cancer, is a “hot” area in cancer thera­peutics. For patients with mul­ti­ple myeloma, im­mune-modulatory drugs and mono­clonal anti­bodies – which exert at least part of their beneficial effect uti­liz­ing this mech­a­nism – are already part of the arsenal of treat­ment op­tions. Now checkpoint in­hib­i­tors seem to be making their mark.

Scientists have found that tumor cells have the mol­e­cules PDL1/PDL2 on their surface. These mol­e­cules send signals through the PD-1 pro­tein on im­mune cells to “inactivate” the im­mune cells, preventing them from eradicating the cancer cells. Checkpoint in­hib­i­tors in­hib­it the inter­action be­tween PD-1 and PDL1/PDL2, thereby “lifting the brake” on im­mune recognition and elimination of cancer cells.

At the ASH meeting in 2014, re­searchers reported that treat­ment with single-agent PD-1 in­hib­i­tor Opdivo (nivolumab) led to stable dis­ease as the best re­sponse in patients with re­lapsed/refractory mul­ti­ple myeloma. However, at the ASH 2015 meeting, Keytruda (pem­bro­lizu­mab), another in­hib­i­tor of PD-1, showed a much more robust re­sponse when com­bined with im­mune-modulatory drugs.

KEYNOTE-023 was a Phase 1/2 study of Keytruda in com­bi­na­tion with Revlimid and dexa­meth­a­sone for patients with re­lapsed/refractory mul­ti­ple myeloma (abstract 505). In this study, the maximally tol­er­ated dose was found to be Keytruda at 200 mg given in­tra­venously every two weeks, along with Revlimid 25 mg given days 1 through 21, and dexa­meth­a­sone 40 mg given weekly. Of 17 patients eval­u­ated, 9 patients (53 per­cent) had a partial re­sponse and 4 patients had a very good partial re­sponse. Among 9 patients with Revlimid-refractory dis­ease, 3 (33 per­cent) had a partial re­sponse, and 2 (22 per­cent) a very good partial re­sponse. The median duration of re­sponse was 9.7 months.

In another study pre­sented at the ASH meeting, Keytruda was com­bined with Pomalyst and dexa­meth­a­sone in patients with re­lapsed/refractory mul­ti­ple myeloma (abstract 506). However, none of the patients were re­frac­tory to prior treat­ment with Pomalyst. In this single-arm Phase 2 study, patients re­ceived 28-day cycles of Keytruda at a dose of 200 mg in­tra­venously every two weeks, plus Pomalyst 4 mg for 21 out of of 28 days, and dexa­meth­a­sone 40 mg weekly. The trial en­rolled 33 patients, of whom 23 (70 per­cent) were re­frac­tory to an immuno­modu­la­tory drug and a pro­te­a­some in­hib­i­tor. An over­all re­sponse rate of 60 per­cent in 27 evaluable patients was observed. The re­sponse rate was 55 per­cent in 20 patients double re­frac­tory to an immuno­modu­la­tory drug and a pro­te­a­some in­hib­i­tor.

At the ASH 2015 meeting, more data emerged on the ef­fec­tiveness of chi­meric an­ti­gen re­cep­tor (CAR) T cells – im­mune cells ge­net­ic­ally modified to recog­nize and eradicate cancer cells that have spe­cif­ic target pro­teins on their surface. 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, and en­rolled patients who had re­lapsed within one year of a prior au­tol­o­gous stem cell trans­plant. Patients re­ceived 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. However, the CD19 target is not found at high levels on most myeloma cells (see re­lated Beacon news).

At the ASH 2015 meeting, a late breaking abstract reported on mul­ti­ple myeloma remissions in the first clin­i­cal trial of a CAR T-cell ther­apy targeting the anti-B cell maturation an­ti­gen (BCMA), a pro­tein pro­duced by nor­mal and malignant plasma cells (abstract LBA-1). During the Phase 1 trial, patient T cells were harvested and ge­net­ic­ally modified to pro­duce the BCMA-targeted CAR T cells. Each patient re­ceived a single in­fusion of their modified T cells after first being admin­istered a chemo­ther­apy regi­men of cyclo­phos­phamide 300 mg/m² and flu­dar­abine 30 mg/m² for three days.

A total of 12 patients were treated. The authors reported that there were two partial re­sponses, one very good partial re­sponse, and one stringent com­plete re­sponse. It appears that re­sponses were more robust at the highest CAR T-cell dose level.

After having achieved “rock-star” status given their robust ac­­tiv­ity in a variety of solid tumors, checkpoint in­hib­i­tors may also be poised to enter the armamentarium of the myelomatologist. In addi­tion, it appears that CAR T-cell ther­apy has finally arrived as well. Patients with mul­ti­ple myeloma will be the winners!

Dr. Ravi Vij is 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.