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ASH 2011 Highlights
ASH 2011 brought the greatest number of abstracts on multiple myeloma (MM) ever published in the meeting’s history, 712 abstracts to be exact. While no single abstract made headlines, taken collectively they offer ample evidence of a year of significant steps forward in understanding, prognosticating, imaging, treating, and monitoring this disease. To better categorize the meeting’s highlights, we turn to the IMF’s 10 STEPS TO BETTER CARE as a framework.
01.19.12

ASH 2011 brought the greatest number of abstracts on multiple myeloma (MM) ever published in the meeting’s history, 712 abstracts to be exact. While no single abstract made headlines, taken collectively they offer ample evidence of a year of significant steps forward in understanding, prognosticating, imaging, treating, and monitoring this disease. To better categorize the meeting’s highlights, we turn to the IMF’s 10 STEPS TO BETTER CARE as a framework.

STEP 1 - KNOW WHAT YOU’RE DEALING WITH

Several important abstracts were presented in this general category of diagnosis and disease definition, notably a series of studies from the Mayo Clinic, Rochester, MN, USA, that examine outcomes among various subgroups of patients.
  • Shaji Kumar examined the outcomes of patients in the US, Europe, and Korea who became refractory to both bortezomib and an immunomodulatory agent. He points out that these “double refractory” patients have a poor prognosis no matter where they are treated, with median overall survival at 13 months in the US, 7 months in Europe, and 8 months in Korea. Patients in the US are likely to have more therapies both before and after they become refractory.
    • Differences in patterns of therapy and outcomes among patients in the US, Europe, and Asia (Dr. Shaji Kumar, Mayo Clinic, Rochester, MN, USA, abstract #3989)
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  • Vishal Rana’s study looking at the reasons for early mortality among those who died within twelve months of diagnosis concludes that advanced age, poor performance status, high ISS stage, and high levels of serum calcium are predictors of early death. Identifying these factors up front will enable doctors to design risk-adapted, appropriate therapy.
    • Factors predicting early mortality in patients with newly diagnosed multiple myeloma (Vishal Rana, Mayo Clinic, Rochester, MN, USA, abstract #3981)

  • Soo-Mee Bang retrospectively examined outcomes in patients over 70 years of age, concluding that exposure to novel agents has improved their overall survival, although it still lags behind that of younger patients.
    • Treatment patterns and outcomes in elderly patients (Soo-Mee Bang, Mayo Clinic, Rochester, MN, USA, abstract #3980)

  • Prashant Kapoor’s analysis of survival among patients 45 years of age or less at the time of diagnosis in the era of novel therapies concludes that younger patients not only benefit from the survival advantage granted by their youth and general good health, but from exposure to novel agents, as opposed to their historical controls.
    • Survival outcome of young myeloma patients in the era of novel therapies (Prashant Kapoor, Mayo Clinic, Rochester, MN, USA, abstract #2950)
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  • Another significant presentation in this category was the follow-up on the study of therapy for high-risk smoldering multiple myeloma (SMM) by Maria-Victoria Mateos, of the University of Salamanca, Salamanca, Spain. Dr. Mateos’s longer-term data now indicate that time to progression to active MM was significantly prolonged in the group of patients with high-risk smoldering disease that was treated with nine cycles of lenalidomide (Revlimid®) and dexamethasone followed by lenalidomide maintenance. The median time to progression to active disease in the untreated group was 25 months, whereas the median has not been reached in the treated group. Only two patients developed second primary malignancies in the treated group, and both malignancies were confirmed to have originated before the start of len/dex therapy. While there is a trend to improved overall survival in the treated group, it is too early to fully assess overall survival benefit, and therefore it is too early to change clinical practice based on these trial results.
    • Smoldering myeloma (SMM) at high risk of progression to symptomatic disease (Maria-Victoria Mateos, Hospital Clinico Universitario, Salamanca, Spain, abstract #991)
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STEP 2 - TESTS YOU REALLY NEED

Data in the category of valuable prognostic tests includes the new heavy/light chain assay, genetic studies, imaging studies, and flow cytometry. Of particular note is the identification of an IMiD-binding protein on the surface of MM cells, cereblon, which corresponds to response to treatment with IMiD therapies.

Elena Zamagni’s prospective study confirms that PET-defined CR is an independent prognostic factor in MM patients treated with up-front novel therapies and autologous transplant. Jens Hillengass from the Heidelberg group reports that the number of focal lesions on whole-body MRI has prognostic value after autologous transplant, but not at diagnosis. Whole-body MRI is not able to discern focal lesions with active MM cells as opposed to osteolyses without active MM.

The serum heavy/light assay, which Heinz Ludwig describes as a “simple test,” is able to measure the relationship between clonal and non-clonal protein in the blood. It increases diagnostic accuracy by allowing the measurement of paraproteins that cannot be measured via other techniques, especially in the case of IgA, which tends to migrate to the beta region with serum protein electrophoresis. It can also identify those patients who are not in true CR, despite evidence to the contrary with IFE.

Herve Avet-Loiseau compared data from whole exome sequencing and cytogenetics and discovered that there was no significant correlation between recurrent chromosomal changes and gene mutations. There was also no correlation between the number of genetic mutations and cytogenetic risk. In his study of chromosomal abnormalities in MM patients > 65 years, he discovered a much lower incidence of t(4;14) in this group, but no significant difference in the occurrence of del(13) or del(17p). As in younger patients, both t(4;14) and del(17p) negatively affect PFS and OS in elderly patients.

Roberto Pessoa Magalhaes of the Salamanca group performed a novel flow cytometric analysis of patients with long-term disease control. He reported that these patients have increased numbers of cytotoxic T-cells and CD56 natural killer (NK) cells.

STEP 3 - INITIAL TREATMENT OPTIONS

Survival continues to improve for newly diagnosed patients. Better induction therapy improves survival. Jesus San Miguel’s 5-year follow-up data on the VISTA trial (VP vs. VMP) demonstrated an overall survival benefit of 13 months, with a 31% reduced risk of death for those on VMP vs. MP. Although VMP did not overcome cytogenetic risk, patients who relapsed on VMP and went on to other therapy still did better on their second therapy than those on MP did. There was no increased risk of second malignancies with VMP.

Philippe Moreau of the IFM presented data on the PK and PD of subcutaneous bortezomib (Velcade®), demonstrating that it has similar pharmacokinetics and pharmacodynamics to intravenous bortezomib. Site of injection (thigh or abdomen) had no impact.

Ruben Niesvizky’s UPFRONT study comparing VD, VTD, and VMP in nearly 500 newly diagnosed patients age >65 years in the community practice setting demonstrated that there is added toxicity and no significant benefit to triplet therapy in an elderly population. There were increased rates of hematologic toxicity with melphalan added to Velcade and dexamethasone, and thalidomide increased the incidence of peripheral neuropathy. Similarly, Rachid Baz’s retrospective study of doublets vs. triplets of novel agents indicated that patients without high-risk cytogenetics had no difference in OS regardless of whether they had two-drug or three-drug regimens. Those with high-risk cytogenetics, however, had worse survival with the intensive three-drug regimens than with two-drug combinations.

Nikhil Munshi, of the Dana-Farber Cancer Institute in Boston, reinforced the theme of “less is more” in the elderly population with his study confirming the efficacy and tolerability of once-weekly Velcade with dexamethasone.

STEP 4 - SUPPORTIVE CARE AND HOW TO GET IT

Data in this category include details about peripheral neuropathy, venous thromboembolism, renal impairment, and the risk factors for the development of second primary malignancies (SPMs).
Paola Tacchetti reviews the experience with bortezomib- and thalidomide- induced peripheral neuropathy (PN). An interesting new finding is the correlation between the likelihood of PN and deregulated expression of genes (GEP) involving nervous system function from assessment of bone marrow plasma cells from patients with VTD-induced PN.

In the final analysis of risk factors for venous thromboembolism, the French group noted increased risk in men, with additional risk for smoking and use of erythropoietic agents (Procrit® or Dorbapoietin®). Although prophylaxis is required with IMiD-based therapy, it was not possible to discriminate added value with low molecular-weight heparin (LMWH) versus use of aspirin, although there was a higher risk of bleeding episodes with aspirin use.

The group from Greece showed that bortezomib-based regimens act more rapidly than IMiD-based therapy in the setting of renal insufficiency and are therefore the preferred choice in this situation for newly diagnosed patients.

The group from the University of Pittsburgh’s careful review of serial bone marrow biopsies demonstrates that the use of lenalidomide does not increase the likelihood of marrow dyspoiesis (MDS [myelodysplastic syndrome]).

The next series of papers evaluates the risk of development of second primary malignancies (SPMs) in patients with MM at different disease stages, with different therapies and in a broad range of settings. It is clear that the MM community as a whole has emerged from its period of collective amnesia on this topic of SPMs, which were first noted with the use of melphalan therapy in the 1970s. The risk of SPMs is linked both to host factors such as increasing age, male sex, and prior or family history of cancer, as well as to the impact of treatment. It is important to note that patients can present with an additional second cancer (either hematologic such as MDS or leukemia or a solid cancer such as lung or breast cancer) simultaneous with (or shortly before) the diagnosis of active myeloma. This onset must be distinguished from SPMs that emerge during the course of subsequent therapy. It is helpful to look at the details of each study evaluating particular therapies. There continues to be an increased risk with the use of melphalan as well as the DCEP regimen (in the IFM 2005 study) as well as, possibly, double versus single high-dose melphalan autotransplant. Bortezomib use does not appear to confer any added risk, as noted in the newly presented data (abstracts #2933 and #3972). It is unclear if any of the novel agents confer any definite added risk except possibly lenalidomide when used along with conventional-dose melphalan (eg MPR regimen: abstract #475) or as consolidation immediately after use of high-dose melphalan (IFM 2005 study). Thus, timing and sequencing do seem to be important in adding to any potential underlying host factors.

But, two key points emerge!

  • Any increased risk of SPMs is clearly offset by substantially improved remission duration (as well as overall survival for some studies). The onset of SPMs has not had a negative impact on overall survival in any of the studies.

  • The development of SPMs is an important aspect of longer survival, especially in more elderly MM patients. Appropriate monitoring and early management are now crucial aspects of ongoing care.

Awareness is key: the amnesia is over! Regular monitoring (once or twice a year), for example utilizing whole body PET/CT scanning, can be a very effective way to assess the ongoing status and risks.

STEP 5 - TRANSPLANT: DO YOU NEED ONE?

Transplant, even in this age of highly effective novel therapies, is still of great value in MM and will remain part of the standard of care for younger patients. Two studies that tip the balance toward high-dose therapy and transplant were Antonio Palumbo’s randomized comparison of MPR vs. transplant (MEL200) and Lijun Dai’s trial of len/dex with and without ASCT. Both studies conclude that although toxicities are higher with high-dose melphalan and stem cell transplant, the data does suggest improved progression-free (Palumbo) and overall (Dai) survival.

Several studies examined the timing, route of administration, and cost of mobilizing stem cells with plerixafor (Mozobil®), demonstrating that it can be given at a more convenient schedule, can be administered intravenously as well as by injection, and that, though costly, it causes fewer problems than cyclophosphamide and thereby reduces hospitalization and overall healthcare costs.

STEP 6 - RESPONSE ASSESSMENT

Bruno Paiva of the Salamanca group identifies a group of patients who require special monitoring and novel treatment strategies after stem cell transplant.

STEP 7 - CONSOLIDATION AND/OR MAINTENANCE     

The notion of continuous therapy for MM has gained credence as the result of several studies examining the role of consolidation and maintenance therapy. PFS was doubled in Antonio Palumbo’s follow-up data on the MM 015 MPR-R trial. In Maria-Victoria Mateos’s trial using VT or VP maintenance after VTP or VMP, both VT and VP improved the complete response rate from 24% before to 42% after maintenance.  The IFM data on up-front VRD followed by ASCT, VRD consolidation, and lenalidomide maintenance led to an impressive stringent complete response (sCR) rate of 38%.

STEP 8 - MONITORING WITHOUT MYSTERY

Saad Usmani from the University of Arkansas provides compelling data on the utility of MRI and PET in predicting PFS and OS. Former IMF grant awardee Marco Ladetto of the University of Torino presented data on the impact of minimal residual disease (MRD) detected by real-time quantitative polymerase chain reaction, and concluded that careful monitoring of increases in MRD can lead to tailored treatment for those most at risk of relapse. In these patients, it is crucial to make response as complete as possible.

STEP 9 - RELAPSE: DO YOU NEED A CHANGE IN TREATMENT?

Assessment of relapse with bortezomib and the IMiDs were the topics of two important studies. Carlos de Larrea from the University of Barcelona identified a sub-group of bortezomib-treated patients with poor prognosis due to DNA methylation, while Enrique Ocio of the University of Salamanca concludes that if a patient is resistant to one IMiD, another IMiD can be effective and should be tried.

STEP 10 - NEW TRIALS

Probably the richest sources of new information at ASH this year were the sessions on results of new drugs in clinical trials. The most promising include the two drugs likely to be approved by the FDA in the next calendar year, carfilzomib and pomalidomide. In Andrzej Jakubowiak’s phase I/II frontline trial of carfilzomib in combination with lenalidomide and dexamethasone, 100% of patients had >/= VGPR after 4 cycles, with 71% of patients in CR after 4 cycles, and 79% in nCR/CR after 12 cycles. All patients were able to mobilize and harvest stem cells for future transplant successfully. The IFM and Dana-Farber data with pomalidomide and dexamethasone in relapsed and refractory MM were also impressive. Other very promising results were from the studies of the monocloncal antibody elotuzumab in combination with lenalidomide and dexamethasone; bendamustine, an old drug finding new life in combination with lenalidomide or bortezomib; and the novel proteasome inhibitors MLN9708, given orally, and marizomib, given intravenously. Perhaps most disappointing were the long-anticipated results of two studies of the HDAC inhibitor vorinostat (Zolinza®),which showed only minimal benefit and significant toxicities.

This overview of the year’s ASH highlights also serves as an introduction to the forthcoming International Myeloma Working Group (IMWG) publications, which will update older guidelines and provide new ones in line with the newly presented data. Among the new guidelines will be:

  • Dimopoulos and Terpos’s update on imaging
  • San Miguel’s analysis of the best of the new drugs, with reference to their mechanisms of action
  • Treatment of patients older than 75 years of age, piloted by Palumbo
  • GEP and High-Risk myeloma, by Chng and Munshi
  • Risk stratification, by Chng, Durie, Lonial, and Chanan-Khan
  • High-risk SMM and diagnostic testing, by Lonial, Kumar, and Rajkumar
  • Secondary Primary Malignancies, by Durie and Crowley
  • Balloon kyphoplasty and bone health, by Malloy, Kyriakou, and Durie
  • ISS and high-dose therapy, by Moreau, Crowley, and Durie
  • Role of supportive care agents, by Chanan-Kahn.

We thus anticipate a year of outstanding contributions to the guidelines for better understanding and management of myeloma, and a year that will bring two new agents to the armamentarium of approved drugs to fight it.

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