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The Myeloma Quiz – July 2014

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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.

Exciting data on the CD38 antibodies daratumumab and SAR650984 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 news article. For the April, 2014 edition of the Myeloma Quiz, follow this link.)

  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 (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).

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

  1. 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 (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.

  1. 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.

  1. 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 (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.

Photo of Dr. Ravi Vij, associate professor of medicine, Washington University School of Medicine in St. Louis.
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  • R said:

    Thanks !

  • Coach Hoke said:

    I believe the continuous maintenance in Dr.Palumbo's study was with Revlimid. Is that correct, or was it combined with dex and what was the dose?

    Coach Hoke

  • Jan Stafl MD said:

    Thank you Dr. Vij for the pop quiz, and the accompanying description of the background studies from this year's ASCO meeting. Unfortunately, I find it hard to be enthusiastic about panobinostat and other HDAC inhibitors, since the PFS was less than four months longer with it, with significant side effects.

    Likewise, the data on the length of PFS with the three CD38 monoclonal antibodies studied so far is rather underwhelming. More studies are of course needed, but it is likely that another approach is needed in addition to the above two avenues of treatment.

    The approach that seems most promising to me, and many immunologists that I have consulted, has been CAR-T therapy. This new therapy targets either CD19 or other proteins with monoclonal antibodies, and genetically engineered T cells from individual patients to target their own malignant plasma cells. Very promising data from acute leukemia and some lymphomas patients are just now leading to studies with MM at U Penn and other institutions.

    Other CAR (Chimeric Antigen Receptor) therapies are starting to be tested even for more common solid tumors (breast, ovarian, prostate). The US FDA has just this month instituted a fast track approval designation for CAR therapies for leukemias and lymphomas, so I hope the multiple myeloma will be next. The possibility of this being a curative therapy for some is certainly intriguing!

    I have to admit that I have a personal stake in this, as I am in the process of possible enrollment in a CAR-T19 clinical trial at U Penn. But I sincerely hope that my experience and the data from it will be valuable to our entire myeloma community, and oncology therapy in general. Many of us may be able to play a role in this and other groundbreaking immunologic approaches. May it be so!

  • Nancy Shamanna said:

    Thanks for the quiz and the explanations too, Dr. Vij. I am trying to 'keep up' with studying the new therapies, and it really is a test of one's knowledge of immunology and cell biology! In the definition of PFS, (progression free survival), how is that defined? Does 'progression' refer to having clinical findings of CRAB criteria, in which case treatment would be reinstated, or does it refer to being able to detect small amounts of the 'M' protein or other markers, that do not yet literally require treatment?

  • Myeloma Beacon Staff said:

    Thanks for the comments, everyone.

    Coach Hoke - Dr. Palumbo's study was an analysis of the results from three trials. Two of those trials included Revlimid as the maintenance therapy. The other study included maintenance with Velcade and thalidomide. The dose of Revlimid used in the two trials with Revlimid maintenance therapy was 10 mg on days 1-21 of a 28-day cycle. No dexamethasone was included in the Revlimid maintenance regimen. The references for the three studies included in the analysis by Dr. Palumbo and his colleagues are as follows:

    "Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival," Palumbo et al., Journal of Clinical Oncology, 2014.

    "Maintenance Therapy With Lenalidomide Significantly Improved Survival Of Young Newly Diagnosed Multiple Myeloma Patients, Gay et al., ASH 2013 Annual Meeting Abstract 2089.

    Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma, Palumbo et al., Palumbo et al, New England Journal of Medicine, May, 2012

    Please also be sure to see all the Beacon's news and opinion articles related to maintenance therapy.

    Jan - In interpreting the progression-free survival outcomes for the monoclonal antibody treatments currently in development, it is worth keeping in mind that most of the studies with them thus far have been carried out in patients who have had many previous lines of therapy. It unfortunately is the case that even very effective therapies, which may substantially increase survival when used early in the treatment of myeloma, may not have much of an impact on PFS when used after many earlier lines of therapy.

    Nancy - The concept of progression, when used in clinical trials to establish a patient's progression free survival, is defined by criteria outlined in each trial's protocol. Usually, the criteria are those recommended by the International Myeloma Working Group, which are discussed in this Beacon forum thread.

    As we note in that thread, the definition is rather complicated, because it needs to take into account many different ways a patient may have responded to their previous therapy. However, "the most common way of thinking of [progression] is that it's a 25 percent increase in the serum M-spike, but the increase has to be at least 0.5 g/dL."

  • Nancy Shamanna said:

    Thanks MBS, then from an sCR to 'progression', one would need to have an M-spike of 0.5 g/dl (5 g/l) to call that progression, from the definitions of the International Myeloma Working Group. Good to know! (This definition would not apply to non-secretory patients though.)

    When one is reading these interesting articles about new research, it is sometimes puzzling as to how to define terms. I really appreciate being able to learn by reading the Beacon's articles!

  • Cheryl G said:

    Thanks, Dr. Vij, for these quizzes. They are really helpful. And thanks, Beacon team, for the feedback on questions people have asked about the quiz.

  • Myeloma Beacon Staff said:

    Jan, the monoclonal antibodies initially will be approved as therapies for relapsed myeloma patients, and that's almost certainly how they will be used predominantly at first.

    But, given their efficacy and side effect profiles and, particularly, given the trials that are being done with them in newly diagnosed patients, we would be surprised if they do not end up being used in front line therapy. Remember, there are Phase 3 trials ongoing, or just about to start recruiting, right now that are testing these agents as therapies for newly diagnosed patients.

    The CAR-T therapies you have mentioned are certainly promising, and nothing we have said is meant to imply otherwise. However, they are also noticeably further back in the development pipeline than the monoclonal antibodies.

  • Jan Stafl MD said:

    I also thank MBS staff for your input, and agree that monoclonal antibodies in current development are likely to be more effective with longer PFS in treatment naive patients. They are important to study and hopefully get approved, but I doubt they will be used as first line therapy.

    My point is that it is unlikely that any of them used alone, or with present novel agents (IMiBs or proteasome inhibitors) will lead to long term remissions in MM. But with CAR-T therapy, and most likely future immunologic approaches, that this elusive outcome, and possibly even cure, will be possible. Again, may it be so!

    In terms of the definition of PFS, an increase of serum free light chains, the finding of new plasmacytomas, or new CRAB signs also qualify in the definition of recurrence. They can also be evidence of MM becoming refractory to treatment (from personal experience).

  • Sylvia B said:

    Dear Dr. Vij,

    Thank you so much for the article and quiz. I learned a lot today about mm. Also, the question and answer section was very helpful.

    Sylvia B.

  • multibilly said:

    I think a really good takeaway of this thread is the comment about keeping in mind which cohort of patients are being used in a trial when looking at PFS data. When reading about a trial, I tend to jump to the PFS and OS data and often lose sight of the fact that many of these newer drugs are being tested on heavily pre-treated patients (which is a worthy effort).

    Jan, you stated that you think it unlikely that the MABs in development will be approved for treatment naive patients (newly diagnosed patients). What makes you say that? I'm intrigued by MABs simply because of their promise of reduced side effects, which any mm patient would welcome, whether they be NDMM or relapsed/refractory.

  • Myeloma Beacon Staff said:

    Multibilly, you're absolutely right. Many people think that, when they're looking at the results of a clinical trial, all that matters when it comes to what sort of patients were in the trial is whether the patients were newly diagnosed or relapsed/refractory.

    That's an important issue, of course. But there's also a big difference between relapsed patients who have had, for example, one to three prior lines of therapy, and relapsed patients who have had four, five, or six prior lines of therapy.

    Many of the larger trials involving relapsed patients typically have inclusion criteria specifying that patients may have had one, two, or three prior lines of therapy, but no more than that. So you almost always see higher response rates and longer survival times in those trials than in smaller trials testing very new drugs in patients with a median of four or more prior lines of therapy.

    In articles about trials involving relapsed patients, The Beacon makes a point of including information about the median number of prior therapies patients in the trial had.

  • Pam McFarlane said:

    Is there a tentative timetable defined for approval on the CD38 drugs. Those of us in the late stages are grasping for straws of hope.

  • Jan Stafl MD said:

    In answer to Multibilly's query, here is the reason I believe newly diagnosed MM patients will continue to be treated for the foreseeable future with novel agents (proteasome inhibitors and IMID's), and steroids, rather than monoclonal antibodies: The efficacy of the current initial treatment is quite impressive, with response rates approaching 100%, and usually acceptable side effects. The monoclonal antibodies being developed I predict will not exceed these initial therapy results, nor increase OS or PFS.

    Their role will likely be in treating refractory disease, when they will be added to novel agents to increase their efficacy. I predict that even daratumumab, which has some efficacy when used alone in recurrent MM, will be used in combination therapy. Multiagent therapy is the most effective approach in refractory MM at this point, because of the various subclones which the B cell derived malignant plasma cells mutate into.

    Of course, they may all be superceeded by new immunotherapeutic approaches in development, which actually have the potential for long lasting CR's, if not true cures of MM. That is my sincere hope!