It’s July, and we have had some time to digest the findings from the American Society of Clinical Oncology (ASCO) annual meeting held in Chicago May 30 through June 3.

Quite a few pre­sen­ta­tions caught one’s eye.

We finally saw the results of the much awaited PANORAMA-1 study in­ves­ti­gating the efficacy and safety of panobinostat ^[1] (LBH589) plus Velcade and dexa­meth­a­sone com­pared to Velcade and dexa­meth­a­sone alone.

Exciting data on the CD38 anti­bodies daratumumab ^[2]and SAR650984 ^[3]continued to emerge at ASCO.

Another study looked at a pro­gres­sion-free sur­vival out­come known as “PFS2,” which measures the time from the start of treat­ment to when the patient ex­peri­ences a second pro­gres­sion.

And finally, results of a ran­dom­ized trial of mel­phalan, pred­ni­sone, and thalido­mide (MPT) versus mel­pha­lan, pred­ni­sone, and Revlimid (MPR) were reported.

So it is time to take another short quiz to test your knowledge about the key ASCO takeaways.  (For a review of the ASCO pre­sen­ta­tions relevant to the quiz, see this Beacon ^[4] news article. For the April, 2014 edition of the Myeloma Quiz, follow this link ^[5].)

1. All of the fol­low­ing state­ments about the PANORAMA-1 study are true except:
1. The addi­tion of panobinostat to Velcade and dexa­meth­a­sone im­proved the com­plete and near com­plete re­sponse­ rates in patients not re­frac­tory to Velcade.
2. The addi­tion of panobinostat to Velcade and dexa­meth­a­sone im­proved pro­gres­sion-free sur­vival by approx­i­mately four months in patients not re­frac­tory to Velcade.
3. The addi­tion of panobinostat to Velcade and dexa­meth­a­sone produced re­sponse­s in patients re­frac­tory to Velcade.
4. The addi­tion of panobinostat to Velcade and dexa­meth­a­sone in­creased the rates of severe diarrhea, fatigue, and low platelet counts.

Correct answer: .

In the PANORAMA-1 trial, 768 patients with re­lapsed or re­lapsed / re­frac­tory multiple myeloma not re­frac­tory to Velcade ^[6] (bor­tez­o­mib), and who had re­ceived one to three prior lines of ther­apy, were ran­dom­ized to treat­ment with panobinostat ^[1], Velcade, and dexa­meth­a­sone ^[7] (Decadron) and com­pared to a group of patients re­ceiv­ing a placebo with Velcade and dexa­meth­a­sone.  Nearly half the patients enrolled in the trial had re­ceived at least two prior regi­mens at the time of ran­dom­i­za­tion.

After a median follow-up of approx­i­mately 125 weeks, the pri­mary end­point of pro­gres­sion-free sur­vival was met, with patients re­ceiv­ing panobinostat having a median pro­gres­sion-free sur­vival of 12 months versus 8.1 months for patients re­ceiv­ing the placebo.

The over­all re­sponse­ rate was 60.7 per­cent in the panobinostat arm versus 54.6 per­cent in the placebo arm.  The com­plete/near com­plete re­sponse­ rates were 27.6 per­cent versus 15.7 per­cent, re­spec­tive­ly.

The benefit in efficacy came at the cost of greater toxicity in the panobinostat arm of the trial.  Severe diarrhea was observed in 25.5 per­cent of patients in the panobinostat arm versus 8 per­cent in the placebo arm.  Severe fatigue was seen in 23.9 per­cent  of patients in the panobinostat arm versus 11.9 per­cent in the placebo arm. Severe low platelet counts were seen in 67.4 per­cent of patients in the panobinostat arm and 31.4 per­cent in the placebo arm.

Patients with dis­ease re­frac­tory to Velcade were not allowed to be enrolled on the PANORAMA-1 study. However, results of the PANORAMA-2 study pub­lished earlier show that 34.5 per­cent of Velcade-refractory patients responded to treat­ment with panobinostat in com­bi­na­tion with Velcade and dexa­meth­a­sone (see related Beacon ^[8] news).

It is now highly likely that panobinostat may be the next drug to be approved by the U.S. Food and Drug Admin­istra­tion in com­bi­na­tion with Velcade for use in patients with multiple myeloma (see related Beacon ^[9] news).

In the future, selective HDAC6-inhibitors such as ACY-1215 ^[10] (ricolinostat ^[11]) may dem­onstrate a better efficacy to toxicity profile.

2. The fol­low­ing state­ment is true about CD38 anti­bodies:
1. Their target can only be found on plasma cells
2. Daratumumab and SAR650984 are “conjugated” anti­bodies
3. They must be com­bined with immuno­modu­la­tory agents such as Revlimid and Pomalyst, or pro­tea­some in­hib­i­tors such as Velcade or Kyprolis, to dem­onstrate efficacy
4. In com­bi­na­tion with Revlimid and dexa­meth­a­sone, they are active in patients re­frac­tory to Revlimid, Pomalyst, Velcade, and Kyprolis.

Correct answer: .

We have so far been lacking a mono­clonal anti­body in the thera­peutic armamentarium of drugs used to treat multiple myeloma. However, it now appears that we may have more than one in contention for the honor.

Additional data about two CD38 mono­clonal anti­bodies, dara­tu­mu­mab and SAR650984, both as single agents and in com­bi­na­tion with Revlimid ^[12] (lena­lido­mide) and dexa­meth­a­sone, were reported at the ASCO annual meeting.

The target for these anti­bodies, the protein CD38, is found in many hema­to­logic malig­nan­cies, in­clud­ing multiple myeloma, non-Hodgkin lym­phoma, acute myeloid leukemia, and chronic lym­pho­cytic leukemia.

Antibodies to proteins such as CD138 and CD56 have been chemically linked to chemotherapeutic agents to form “conjugated anti­bodies.” These agents, which have been tested in clin­i­cal trials for the treat­ment of myeloma, rely on their chemotherapeutic “payload” for the majority of their activity.  CD38 anti­bodies, on the other hand, are “naked anti­bodies” that rely on the patient’s immune sys­tem and the anti­body itself for their activity.

Another mono­clonal anti­body, elotuzumab, targets the protein CS-1 on plasma cells.  Although it appears to have impressive rates of re­sponse­ and pro­gres­sion-free sur­vival when com­bined with Revlimid and dexa­meth­a­sone, it has not shown single agent activity in clin­i­cal trials with myeloma patients.

In contrast, both dara­tu­mu­mab and SAR650984 are active as single agents, even in patients who have re­ceived prior treat­ment with immuno­modu­la­tory agents and pro­te­a­some in­hib­i­tors. Data pre­sented at the ASCO annual meeting showed that this class of agents in com­bi­na­tion with Revlimid was active even in patients re­frac­tory to Revlimid, Pomalyst ^[13] (poma­lido­mide, Imnovid), Velcade, and Kyprolis ^[14] (car­filz­o­mib).

Monoclonal anti­bodies may provide the next big leap in im­prov­ing out­comes of multiple myeloma patients. The ASCO pre­sen­ta­tions about the two agents provide rationale for con­tinued enthusiasm about them.

3. All of the fol­low­ing state­ments about PFS2 are true except:
1. It is longer than PFS1
2. It denotes pro­gres­sion-free sur­vival from first pro­gres­sion to second pro­gres­sion
3. Results of a meta-analysis show that PFS2 was longer for patients re­ceiv­ing con­tin­uous ther­apy com­pared to those re­ceiv­ing fixed duration ther­apy in the front­line setting
4. Results of a meta-analysis show that PFS2 may be a surrogate for over­all sur­vival.

Correct answer: .

PFS1 is defined as pro­gres­sion-free sur­vival from time of initial ran­dom­i­za­tion on a study to first pro­gres­sion. PFS2 is defined as pro­gres­sion-free sur­vival from the time of initial ran­dom­i­za­tion on a study to when the patient ex­peri­ences a second pro­gres­sion. PFS2 has recently emerged as a novel end­point to assess the efficacy of treat­ment regi­mens. PFS2 should not be confounded with “second PFS,” which is defined as the time fromfirst pro­gres­sion to second pro­gres­sion.

At the ASCO meeting, Dr. Antonio Palumbo of the University of Torino reported on PFS1, PFS2, and over­all sur­vival end­points in newly diag­nosed multiple myeloma patients re­ceiv­ing con­tin­uous treat­ment versus those re­ceiv­ing fixed duration of ther­apy

The analysis was based on data from 1,118 patients who had been treated in three Phase 3 trials com­par­ing con­tin­uous versus fixed duration of treat­ment. The three trials com­pared VMPT-VT versus VMP, MPR/MEL 200-R versus MPR/MEL200, and MPR/R versus MPR versus MP.

A one-year landmark analysis showed that the median PFS1 for patients re­ceiv­ing con­tin­uous ther­apy was 32 months versus 16 months for those re­ceiv­ing fixed duration ther­apy.  The median PFS2 for patients re­ceiv­ing con­tin­uous ther­apy was 55 months versus 40 months for those re­ceiv­ing fixed duration ther­apy.  The median second PFS was 15 months in both treat­ment groups. Four-year over­all sur­vival was also superior in patients re­ceiv­ing con­tin­uous ther­apy (69 per­cent) com­pared to patients re­ceiv­ing fixed duration ther­apy (60 per­cent).

This data sug­gests that con­tin­uous ther­apy in the front­line setting may be superior to fixed duration, and that PFS2 may be a surrogate for over­all sur­vival in trials of newly diag­nosed patients with multiple myeloma.

4. The fol­low­ing state­ment is true about the E1A06 intergroup study com­par­ing mel­phalan, pred­ni­sone and Revlimid (MPR) to mel­phalan, pred­ni­sone and thalido­mide (MPT) in newly diag­nosed patients:
1. Patients treated with MPR had a higher re­sponse­ rate than patients treated with MPT
2. Patients treated with MPR had superior pro­gres­sion-free sur­vival than patients treated with MPT
3. Patients treated with MPR had superior over­all sur­vival than patients treated with MPT
4. Patients treated with MPR ex­peri­enced fewer severe side effects than patients treated with MPT.

Correct answer: .

E1A06 was an intergroup Phase 3 ran­dom­ized con­trolled trial com­par­ing mel­phalan, pred­ni­sone, and thalidomide ^[15] (Thalomid) versus mel­phalan, pred­ni­sone and Revlimid in newly diag­nosed multiple myeloma patients who were not can­di­dates for stem cell trans­plan­ta­tion.

The patients re­ceived the three-drug induction regi­mens for a planned 12 cycles and then con­tinued treat­ment with thalido­mide and Revlimid, re­spec­tive­ly, until dis­ease pro­gres­sion.

Overall, 64 per­cent of patients in the MPT arm and 60 per­cent of patients in the MPR arm achieved at least a partial re­sponse­, and 19 per­cent and 23 per­cent, re­spec­tive­ly, achieved at least a very good partial re­sponse­.

The pro­gres­sion-free sur­vival was 21 months for the MPT arm and 18.7 months for the MPR arm.

After a median follow up of 41 months, the median over­all sur­vival was 52.6 months in the MPT arm and 47.7 months in the MPR arm.

The rates of severe side effects were lower in the MPR arm.

The practical implications of this study are limited in the United States as mel­phalan-based regi­mens are now rarely used in newly diag­nosed patients.

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.