Although this year's annual meeting of the American Society of Clinical Oncology (ASCO) started last Friday, the first myeloma-related presentations at the meeting did not take place until Saturday afternoon, the second day of the conference.

The presentations Saturday were given as part of a single education session titled “Multiple Myeloma: Advances in Diagnostics and Management.”

Education sessions, it should be pointed out, are different than most of the sessions that typically take place at scientific meetings such as ASCO.

During the majority of sessions at such meetings, scientists are expected to present and discuss their latest research findings.  Thus, the sessions typically feature updates from ongoing clinical trials or results from recently completed laboratory research.

Education sessions, on the other hand, are an opportunity for experts to "educate" their colleagues about key topics in a particular field, such as multiple myeloma.

As a result, the presentations during an education session take a broader view, reviewing and summarizing evidence from a wide range of studies relevant to the topic being addressed.

An education session presentation is therefore an excellent way to get quickly "up to speed" about a particular topic.

There were three presentations during Saturday's myeloma-related education session.  Each of the presentations is summarized below.

Initial Therapy

The first presentation during the education session was given by Dr. Donna Reece from the Princess Margaret Hospital in Toronto.  Her presentation, which was titled “Update on the Initial Therapy of Multiple Myeloma,” was a detailed discussion of the many treatment options available to newly diagnosed myeloma patients.

In her presentation, Dr. Reece took a broad view of what is meant by "therapy" for newly diagnosed patients.  She did not focus solely on the initial (induction) therapy given to newly diagnosed patients.  Instead, she also discussed options for consolidation therapy and maintenance therapy -- treatment options which are becoming increasingly common among myeloma patients.

The definition of maintenance therapy, Dr. Reece explained, has been standardized.  It is “any treatment administered after the completion of induction therapy in patients whose disease is either responsive or non-progressive, with the goal of prolonging survival.”

The definition of consolidation therapy, on the other hand, is not yet standardized. However, Dr. Reece explained that it usually is relatively intensive short-term therapy administered after a stem cell transplant.

Dr. Reece discussed the evidence related to induction therapy, maintenance therapy, and consolidation therapy (as appropriate) for two broad groups of patients: those eligible for a stem cell transplant, and those ineligible for a transplant.

When she introduced this framework for her presentation, however, she admitted that, in the U.S., “there is a blurring of the distinction” between treatment for these two groups of patients.

Whereas in Canada and Europe, most transplant-eligible patients go on to receive a transplant soon after induction therapy, this is not the case in the U.S.  Instead, many "transplant-eligible" myeloma patients in the U.S. delay transplantation until they relapse after their initial therapy.

As a result, decisions in the U.S. about initial treatment for myeloma are not as often linked, as they are elsewhere, to whether or not a patient is transplant eligible.

Dr. Reece began her review of treatment for transplant-eligible patients by noting that, prior to the availability of novel myeloma therapies such as thalidomide (Thalomid), Velcade (bortezomib), or Revlimid (lenalidomide), a standard induction therapy for these patients was a combination of vincristine (Oncovin), doxorubicin (Adriamycin), and dexamethasone (Decadron), abbreviated as VAD.

This combination achieved an overall response rate of around 80 percent and, when combined with transplantation, led to a median progression-free survival of about 2 years after diagnosis.

With the introduction and use of novel agents in induction therapy for these patients, however, response rates prior to transplantation crept upwards.  In fact, they have approached nearly 100 percent for some three-drug combinations involving one or more novel agents, including cyclophosphamide (Cytoxan), Velcade, and dexamethasone (CyBorD, or VCD) (see related Beacon news), and Velcade, Revlimid, and dexamethasone (VRD) (see related Beacon news).

Induction therapy with novel agents also increased progression-free survival to approximately three years.

The availability of the first orally administered novel agent, thalidomide, also sparked interest in maintenance therapy after stem cell transplantation, given the convenience of using an oral drug for such purpose.  However, the side effects of thalidomide therapy made it a difficult drug for patients to take it for extended periods of time (see related Beacon news).

Revlimid, on the other hand, has proven to be better tolerated over extended periods of time, and studies of its use as maintenance therapy have shown significant improvements in progression-free survival and, in at least one trial, significant improvements in overall survival as well (see related Beacon news).

The success of different maintenance regimens in lengthening progression-free survival, combined with the successful use of consolidation therapy in other blood cancers, sparked interest in using consolidation therapy in multiple myeloma -- often followed by maintenance therapy as well.

There have not yet been many trials investigating the potential benefit of consolidation therapy.  However, Dr. Reece reported that a French trial looking at a therapy plan involving VRD induction, stem cell transplantation, VRD consolidation, and one year of Revlimid maintenance, will soon be reporting a three-year progression-free survival rate of 77 percent and a three-year overall survival rate of 100 percent.

Dr. Reece concluded her discussion of therapy for transplant-eligible patients not so much by recommending a specific set of treatments or a specific treatment regimen.  Instead, she noted that novel agents have improved induction therapy outcomes for these patients, and she also believes there is value in post-transplant therapy with novel agents.

Turning to transplant-ineligible patients, Dr. Reece noted that the introduction of novel agents led to trials combining one or more novel agents with the traditional melphalan (Alkeran) plus prednisone regimen.  This approach has led to a doubling, or greater, in the overall response rate for induction therapy, and a lengthening of progression-free survival to two years and beyond.

Eventually in Europe, regimens such as Velcade, melphalan, and prednisone (VMP), and melphalan, prednisone, and thalidomide (MPT) became common induction therapies, with VMP appearing to be the better tolerated of the two regimens.

In the United States, in contrast, induction therapy for transplant ineligible patients has moved strongly toward Revlimid plus dexamethasone, Velcade plus dexamethasone, or Velcade and dexamethasone combined with either cyclophosphamide or Revlimid.

All three of the novel agents also have been explored as potential maintenance therapies for transplant ineligible patients, and data once again show that such therapy further improves progression-free survival and, in one study, overall survival as well.  Dr. Reece’s assessment, however, is that thalidomide probably has too many side effects to be useful as maintenance therapy in this patient group.

For transplant-ineligible patients with aggressive disease or kidney problems, Dr. Reece typically recommends Velcade-based induction therapy .  She believes two-drug combinations, particularly Revlimid plus low-dose dexamethasone, are the appropriate approach for transplant-ineligible patients who are frail or have other health issues.

Dr. Reece has made the slides for her presentation available for download and viewing as a courtesy to The Beacon’s readers.  A full-text article (PDF) summarizing her presentation is also available.

Treatment Of Double Refractory Patients

Dr. Robert Orlowski from the MD Anderson Cancer Center in Houston gave the second presentation during the education session.  It was titled “Novel Approaches to Treatment of Double-Refractory Multiple Myeloma.”

His talk focused on the development of therapeutic options for "double refractory" myeloma patients -- that is, patients who have relapsed after, or stopped responding to, treatment with both Velcade and Revlimid.

Currently, double refractory myeloma patients have a poor prognosis and limited treatment options.  According to one recent study cited by Dr. Orlowski, this subset of patients has a median progression-free survival of 5 months and a median overall survival of 9 months.

Dr. Orlowski discussed several strategies for improving treatment options for double refractory patients: developing new, more effective members of existing classes of drugs; combining drugs from existing classes of drugs; developing novel agents with new mechanisms of action, and leveraging a better understanding of drug resistance in individual patients.

Kyprolis (carfilzomib) and Pomalyst (pomalidomide) represent two promising novel agents that were recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed and refractory multiple myeloma.

Kyprolis is a proteasome inhibitor, in the same class of drugs as Velcade. Unlike its predecessor, however, it generally does not have high rates of peripheral neuropathy, a condition characterized by pain and tingling in the extremities.

In the Phase 2 trial that led to Kyprolis's approval by the FDA, treatment with the drug led to an overall response rate of 15 percent in double refractory myeloma patients, and was well-tolerated in this heavily pretreated patient group (see related Beacon news).

Pomalyst, along with Revlimid and thalidomide, belongs to the class of drugs known as immunomodulatory agents. Thus far, Pomalyst has had promising results as both a single agent and in combination with dexamethasone in relapsed and refractory myeloma patients, according to Dr. Orlowski.

Results from the recent MM-002 Phase 2 study showed that double refractory myeloma patients treated with Pomalyst plus low-dose dexamethasone had a median overall survival of 13.5 months (see related Beacon news).

While Kyprolis and Pomalyst are yielding encouraging results in heavily pretreated myeloma patients, Dr. Orlowski points out that "we also need new drugs in new classes."

ARRY-520, a kinesin spindle protein inhibitor, is one such drug, which acts against myeloma by interfering with cell division.

It is being explored in clinical trials as both a single agent and in combination with dexamethasone (see related Beacon news).

Results from a recent study of ARRY-520 in myeloma patients with a median of 10 prior lines of therapy showed that treatment with ARRY-520 alone led to an overall response rate of 16 percent. Furthermore, patients in this study who were treated with ARRY-520 plus dexamethasone had an overall response rate of 22 percent.

According to Dr. Orlowski, daratumumab may be the most promising new agent for double refractory myeloma patients. Daratumumab binds to a protein found on the surface of myeloma cells, then signals the immune system to kill the cells.  In recognition of daratumumab's promise, the FDA recently designated the drug a “breakthrough therapy” (see related Beacon news).

In addition to developing more effective treatment regimens, Dr. Orlowski pointed out that there is a need for a better understanding of drug resistance and myeloma-related biomarkers, which may help identify patients who would benefit most from particular therapies.

Cereblon, for example, is a biomarker that has recently attracted the attention of myeloma researchers (see related Beacon news). The activity of immunomodulatory agents such as Revlimid, thalidomide, and Pomalyst appears to depend on a patient's cereblon levels.

A recent study demonstrated that patients with low levels of cereblon appear less likely to benefit from maintenance therapy with thalidomide and initial therapy with Revlimid plus dexamethasone.

Dr. Orlowski also has made the slides for his presentation available for download and viewing as a courtesy to The Beacon’s readers.  In addition, a full-text article (PDF) summarizing his presentation is available.

Tools For Diagnosing And Monitoring Multiple Myeloma

Dr. Jesús San-Miguel from the University Hospital in Salamanca, Spain, gave the final talk of Saturday's education session.  His presentation was titled  “New Tools for Diagnosis and Monitoring of Multiple Myeloma.”

Dr. San-Miguel began his presentation with a brief discussion of standard methods currently used to diagnose myeloma patients and establish their prognosis.

These methods include: establishing the patient’s health history and conducting a physical examination; carrying out tests to determine blood counts and blood chemistry; using serum- and urine-based testing to measure immunoglobulin and free light chain levels; conducting an (x-ray) skeletal survey to assess the extent of bone damage; and using a bone marrow sample to determine marrow composition and to test for chromosomal abnormalities (via a FISH test).

The rest of Dr. San-Miguel’s presentation covered the main topic of his discussion: new diagnostic and prognostic methods.  He divided those methods into two groups: “outside the bone marrow” methods, and “inside the bone marrow” methods.

The new “outside the bone marrow” methods include the heavy-light chain blood assay and MRI, CT, and PET scans.

The heavy-light chain blood assay, Dr. San-Miguel said, “is a very exciting test” that makes it possible to measure the levels of the different heavy and light protein chains in a patient’s blood.  Ongoing research already is indicating that such measurements can shed light on a patient's prognosis.

As for the new types of bone and body scans, Dr. San-Miguel noted that there is need for alternative scanning methods because x-rays are not as sensitive as one might wish.  X-rays only detect the presence of a bone lesion when at least 30 percent of the bone’s substance has been lost, he said.

MRI scans are already considered mandatory in certain situations, he explained, such as the detailed evaluation of a painful bone area.  CT scans also are helpful in situations such as when a patient has bone pain, but there is no sign of a bone lesion.

As for PET scans, Dr. San-Miguel does not recommend them for routine use, although he finds them very valuable in cases where a patient is suspected of having myeloma tumors outside of the bone (extramedullary disease).

All of the newer scanning methods, Dr. San-Miguel noted, have been shown to provide results that shed light on a myeloma patient’s prognosis.

The next part of Dr. San-Miguel’s presentation focused on “inside the bone marrow” diagnostic and prognostic methods.  Those methods include techniques to characterize the genetic characteristics of a patient’s myeloma, and methods for assessing how fully free of disease a patient is after undergoing treatment.

Currently, FISH testing is the main method used by physicians to assess the “genetic” aspects of a patient’s myeloma cells.  The test determines the presence or absence of chromosomal abnormalities in a patient’s myeloma cells, and this information, in turn, is useful for establishing a patient’s prognosis.

New approaches for assessing similar kinds of information include the use of single nucleotide polymorphism (SNP) arrays and gene expression profiling (GEP).

Dr. San-Miguel believes that the use of SNP arrays “will probably become routine” in the near future because the method provides information about important chromosomal abnormalities.

He is less optimistic, on the other hand, about the near-term usefulness of GEP. “I do not think gene expression profiling will be in the clinic in the upcoming years,” he said.

The problem with GEP, he explained, is that the GEP-related results produced thus far by different research centers do not reproduce one another.  “We need standardization” in regard to the methodology, he said.

Next, Dr. San-Miguel turned to new methods that help physicians determine how fully myeloma patients have responded to their treatment.

In particular, these techniques use cells from a patient’s bone marrow to assess whether a patient who has achieved a complete response, based on urine or blood immunoglobulin levels, has any remaining residual disease.

Patients who have no residual disease are described as being “minimal residual disease negative”, or MRD-, while those with signs of residual disease in their marrow are categorized as MRD+.

Two relatively established methods for determining MRD status are polymerase chain reaction (PCR) testing and multiparameter flow cytometry (MFC) testing.  A newer approach is known as next generation sequencing (NGS).

Dr. San-Miguel presented a wide range of clinical trial results showing that MRD status has an important effect on a myeloma patient’s prognosis. Patients who achieve MRD- status have a noticeably better prognosis than those who do not.

He also shared data indicating that the different approaches to assessing MRD status generally come up with similar results.

One major hindrance to the broader use of MRD status at this time, Dr. San-Miguel noted, is that there is still a significant lack of standardization related to the assessment.  This is very much needed, he said, since the method has such significant potential.

In the conclusion to his presentation, Dr. San-Miguel said that the new methods he described in the presentation have significant promise.  Nevertheless, he urged the audience to remember the value of established diagnostic and prognostic methods, particularly the measurement of immunoglobulin levels using blood and urine samples.

Dr. San-Miguel has made the slides for his presentation available for download and viewing as a courtesy to The Beacon’s readers.  A full-text article (PDF) summarizing Dr. San-Miguel's presentation also is available.

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Myeloma presentations from Day 3 and Day 4 will also be summarized in Beacon ASCO daily updates to be published in the upcoming days.  Additional coverage of key research results from the meeting will continue after the meeting is over with individual, topic-specific news articles.  For all Beacon articles related to this year’s ASCO meeting, see The Beacon’s full ASCO 2013 coverage.

Note: Electronic copies of conference presentations and posters made available to the Beacon's readers are for personal use only. Further transmission or publication of the files is not permitted, although hyperlinks to the files are permitted with attribution to the author and to The Beacon (for example, "courtesy of Dr. Jane Doe and The Myeloma Beacon.")