The Myeloma Quiz – July 2014
Published: Jul 23, 2014 2:56 pm
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 (LBH589) plus Velcade and dexamethasone compared to Velcade and dexamethasone alone.
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 news article. For the April, 2014 edition of the Myeloma Quiz, follow this link.)
- All of the following statements about the PANORAMA-1 study are true except:
- The addition of panobinostat to Velcade and dexamethasone improved the complete and near complete response rates in patients not refractory to Velcade.
- The addition of panobinostat to Velcade and dexamethasone improved progression-free survival by approximately four months in patients not refractory to Velcade.
- The addition of panobinostat to Velcade and dexamethasone produced responses in patients refractory to Velcade.
- 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 (bortezomib), and who had received one to three prior lines of therapy, were randomized to treatment with panobinostat, Velcade, and dexamethasone (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 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 news).
- The following statement is true about CD38 antibodies:
- Their target can only be found on plasma cells
- Daratumumab and SAR650984 are “conjugated” antibodies
- They must be combined with immunomodulatory agents such as Revlimid and Pomalyst, or proteasome inhibitors such as Velcade or Kyprolis, to demonstrate efficacy
- 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 (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 (pomalidomide, Imnovid), Velcade, and Kyprolis (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.
- All of the following statements about PFS2 are true except:
- It is longer than PFS1
- It denotes progression-free survival from first progression to second progression
- 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
- 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.
- 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:
- Patients treated with MPR had a higher response rate than patients treated with MPT
- Patients treated with MPR had superior progression-free survival than patients treated with MPT
- Patients treated with MPR had superior overall survival than patients treated with MPT
- 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 (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.
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