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The Myeloma Quiz – January 2015
By: Ravi Vij, M.D.; Published: January 30, 2015 @ 3:07 pm | Comments Disabled
A new year is upon us. I hope it has started well for everybody, and that all had a great holiday season!
The last few weeks of 2014 were a happening time for the multiple myeloma community. The short span of time witnessed the publication of updated criteria for the diagnosis of multiple myeloma from the International Myeloma Working Group (IMWG). In addition, the 56th annual meeting of the American Society of Hematology (ASH) took place in San Francisco, with literally hundreds of myeloma-related oral and poster presentations.
Therefore, it is again time to take a little quiz to test one’s grasp of the new developments. So here goes.
Correct answer: .
The IMWG’s revised criteria for the diagnosis of multiple myeloma include validated biomarkers (indicators of the disease’s presence) in addition to requirements for end-organ dysfunction that had been included in the previous criteria (abstract [1], related Beacon [2] physician column).
The rationale for updating the diagnostic criteria was that the previous definition of myeloma required a clinical manifestation of serious end-organ damage before the diagnosis could be made. This definition prevented patients from getting early therapy to prevent organ damage from occurring in the first place.
Two changes in the tools we have available to diagnose, treat, and monitor multiple myeloma motivated the development of the new diagnostic criteria.
First, we now have less toxic and more effective treatment options, some of which have early data showing a possible improvement in survival when used in patients who previously would have been diagnosed as having smoldering myeloma.
Second, there have been significant advances in laboratory and imaging techniques used in the diagnosis and monitoring of multiple myeloma.
The IMWG reached a consensus that, if reliable biomarkers could be identified for patients with smoldering myeloma that predicted an 80 percent probability of progression to symptomatic myeloma within two years, such patients should be redefined as having multiple myeloma and be offered therapy.
With this goal in mind, the panel – after data mining and reviewing published data – came up with the recommendation that the definition of multiple myeloma be expanded to include one or more of the following biomarkers of malignancy:
Also, it was recommended that bone lesions should be defined as one or more osteolytic lesions seen not only on skeletal survey, but also if detected by CT or PET/CT scanning.
Correct answer: .
The ASPIRE trial was a randomized, open-label, multicenter Phase 3 study of Kyprolis [3], Revlimid, and dexamethasone versus Revlimid and dexamethasone in patients with relapsed multiple myeloma (ASH abstract [4], slide deck [5], related journal article abstract [6], related Beacon [7] news).
The primary end point – progression-free survival – was statistically superior for Kyprolis, Revlimid [8], and dexamethasone [9] (KRd) (26.3 months) compared to Revlimid and dexamethasone (Rd) (17.6 months). With a median follow up of 32 months, the median overall survival was not reached in either arm. The overall survival difference did not meet the level of significance pre-specified in the trial protocol.
Safety analysis showed similar rates of trial discontinuation due to adverse events (KRd 15.3 percent versus Rd 17.7 percent). Other side effects occurred at similar rates in the two arms: dyspnea (shortness of breath) (KRd 19.4 percent versus Rd 14.9 percent), heart failure (KRd 6.4 percent versus Rd 4.1 percent), coronary artery disease (KRd 5.9 percent versus Rd 4.6 percent), and acute kidney failure (KRd 8.4 percent versus Rd percent). There appeared to be a higher rate of high blood pressure in the KRd arm (14.3 percent versus 6.9 percent).
A measure of overall patient quality of life, known as EORTC global health status, improved in the KRd group versus the Rd group over 18 cycles of treatment.
Correct answer: .
Elotuzumab [10], a monoclonal antibody to the SLAM7 or CS1 antigen produced by malignant plasma cells and natural killer (NK) cells, is postulated to kill myeloma cells by encouraging the body’s immune system to attack the myeloma cells. This is known as an “immune-mediated attack.”
At the ASH 2014 annual meeting, final results of the Phase 1b/2 study of elotuzumab with Revlimid and dexamethasone in relapsed and refractory multiple myeloma were reported. In the Phase 2 portion of the study, patients were randomized to receive either 10 mg/kg or 20 mg/kg of elotuzumab.
The overall response rate was 92 percent in the 10 mg/kg cohort and 76 percent in the 20 mg/kg cohort. Median progression-free survival also was higher in the lower-dose cohort (32.4 months versus 25 months) (abstract [11]). Results of the ELOQUENT-2 study randomizing patients to either elotuzumab (10 mg/kg) with Revlimid and dexamethasone, or Revlimid and dexamethasone alone, are now eagerly awaited.
The antigens CD38 and CD138 are both produced by multiple myeloma cells. Daratumumab [12] and SAR650984 [13] are antibodies to CD38. In contrast to elotuzumab, these drugs are postulated to exert their anti-myeloma activity via both an immune–mediated attack and direct effects on myeloma cells. Phase 1/2 trials of both these antibodies in combination with Revlimid and dexamethasone in relapsed and refractory multiple myeloma were reported at the ASH 2014 meeting.
In the trial of daratumumab with Revlimid and dexamethasone, patients had a median of two prior lines of therapy. Patients who were refractory (resistant) to Revlimid, or could not tolerate the drug, were excluded from the study. In the Part 1 dose escalation portion of the study, doses were escalated from 2 mg/kg to 16 mg/kg and, in the Part 2 expansion cohort, patients were treated at 16 mg/kg.
With a median follow up of 12.9 months, the overall response rate in Part 1 of the study was 100 percent, with complete responses in 31 percent of the patients, and very good partial responses in 46 percent. With a median follow up of 5.6 months in Part 2 of the study, the overall response rate was 86.7 percent, with complete response in 6.7 percent and very good partial responses in 43 percent. No dose-limiting toxicities were reported (abstract [14], slide deck [15], related Beacon [16] news).
In the Phase 1b dose escalation trial of SAR650984 in combination with Revlimid and dexamethasone, patients were treated with 3 mg/kg, 5 mg/kg, and 10 mg/kg of SAR650984. This trial allowed patients refractory to a variety of agents, including Revlimid. Patients had received up to a median of 7 to 10 prior treatment regimens.
Again, the drug combination was well tolerated. For patients treated at the 10 mg/kg dose, the overall response rate was 63 percent, with 29 percent of patients having a very good partial response. Responses were seen in 48 percent of patients refractory to Revlimid, 44 percent of patients refractory to Velcade [17] (bortezomib), 40 percent of patients refractory to Kyprolis, and 33 percent of patients refractory to Pomalyst [18] (pomalidomide, Imnovid) (abstract [19], slide deck [20], related Beacon [21] news).
Correct answer: .
As more data emerges supporting the utility of maintenance therapy after both transplant and conventional therapy for patients with multiple myeloma, the development of oral proteasome inhibitors would provide a convenient mode for long-term treatment.
Ixazomib [22] and oprozomib [23] are both oral proteasome inhibitors in development. At the ASH 2014 meeting, results were reported from a Phase 2 study of ixazomib maintenance following ixazomib, Revlimid and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma.
Though a significant number of patients had side effects and required dose-reductions, a median of 31 cycles of ixazomib were delivered, and the median number of maintenance cycles was 19. Ninety percent of patients achieved a partial response or better, with 59 percent having a very good partial response, and 22 percent a complete response after up to 12 cycles of induction. Ixazomib maintenance improved response, with 48 percent of patients showing increased response depth during maintenance (abstract [24], slide deck [25], related Beacon [26] news).
Phase 3 trials of ixazomib with Revlimid and dexamethasone versus placebo plus Revlimid and dexamethasone, in both previously treated and untreated multiple, are currently enrolling (TOURMALINE-MM 1 and 2).
Oprozomib is currently in Phase 1/ 2 development. At the ASH 2014 meeting, it was reported that the majority of patients treated with the drug experienced gastrointestinal toxicity with nausea, vomiting, and diarrhea. However, it appeared that, with modifications to the dosing formulation and introduction of a stepped up schedule, the toxicity issues that have plagued the development of oprozomib may be getting more manageable.
Overall response rates of 31.3 percent on a 2-out-of-7 day schedule, and 23.3 percent on a 5-out-of-14 day schedule, were observed. The overall response rate in 11 Kyprolis-refractory patients in the Phase 2 portion study was 18.2 percent (abstract [27], slide deck [28], related Beacon [29] news).
Also at the ASH 2014 meeting, data were presented on Imbruvica [30], a Bruton’s tyrosine kinase inhibitor, and selinexor [31], an inhibitor of the nuclear export protein XPO-1. One quarter of the patients treated on the highest dose of Imbruvica (840 mg daily) with weekly dexamethasone demonstrated a clinical benefit (abstract [32], slide deck [33], related Beacon [34] news). The drug was well tolerated. Selinexor with dexamethasone led to responses in six of nine patients. However, adverse events included nausea, vomiting, anorexia, fatigue, and weight loss in a significant proportion of patients (abstract [35]).
Ricolinostat [36] (ACY-1215) is an oral selective histone deacetylase 6 inhibitor. At the ASH 2014 meeting, ricolinostat in combination with Velcade and dexamethasone (abstract [37]), and in combination with Revlimid and dexamethasone (abstract [38]), demonstrated responses in 45 percent and 64 percent of patients with relapsed and refractory multiple myeloma, respectively. Toxicities were generally manageable.
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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URL to article: https://myelomabeacon.org/news/2015/01/30/myeloma-quiz-january-2015/
URLs in this post:
[1] abstract: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2970442-5/abstract
[2] Beacon: https://myelomabeacon.org/news/2014/10/26/new-multiple-myeloma-diagnostic-criteria/
[3] Kyprolis: https://myelomabeacon.org/tag/kyprolis/
[4] ASH abstract: https://ash.confex.com/ash/2014/webprogram/Paper70771.html
[5] slide deck: https://myelomabeacon.org/docs/ash2014/79.pdf
[6] journal article abstract: http://www.nejm.org/doi/full/10.1056/NEJMoa1411321
[7] Beacon: https://myelomabeacon.org/news/2014/12/10/ash-2014-multiple-myeloma-update-day-two-education-session-midday-oral-session/#ASPIRE
[8] Revlimid: https://myelomabeacon.org/resources/2008/10/15/revlimid/
[9] dexamethasone: https://myelomabeacon.org/resources/2008/10/15/dexamethasone/
[10] Elotuzumab: https://myelomabeacon.org/tag/elotuzumab/
[11] abstract: https://ash.confex.com/ash/2014/webprogram/Paper74278.html
[12] Daratumumab: https://myelomabeacon.org/tag/daratumumab/
[13] SAR650984: https://myelomabeacon.org/tag/sar650984/
[14] abstract: https://ash.confex.com/ash/2014/webprogram/Paper74400.html
[15] slide deck: https://myelomabeacon.org/docs/ash2014/84.pdf
[16] Beacon: https://myelomabeacon.org/news/2014/12/10/ash-2014-multiple-myeloma-update-day-two-education-session-midday-oral-session/#Daratumumab
[17] Velcade: https://myelomabeacon.org/resources/2008/10/15/velcade/
[18] Pomalyst: https://myelomabeacon.org/tag/pomalyst/
[19] abstract: https://ash.confex.com/ash/2014/webprogram/Paper71786.html
[20] slide deck: https://myelomabeacon.org/docs/ash2014/83.pdf
[21] Beacon: https://myelomabeacon.org/news/2014/12/10/ash-2014-multiple-myeloma-update-day-two-education-session-midday-oral-session/#SAR650984
[22] Ixazomib: https://myelomabeacon.org/tag/ixazomib/
[23] oprozomib: https://myelomabeacon.org/tag/oprozomib/
[24] abstract: https://ash.confex.com/ash/2014/webprogram/Paper69951.html
[25] slide deck: https://myelomabeacon.org/docs/ash2014/82.pdf
[26] Beacon: https://myelomabeacon.org/news/2014/12/10/ash-2014-multiple-myeloma-update-day-two-education-session-midday-oral-session/#Ixazomib
[27] abstract: https://ash.confex.com/ash/2014/webprogram/Paper75523.html
[28] slide deck: https://myelomabeacon.org/docs/ash2014/34.pdf
[29] Beacon: https://myelomabeacon.org/news/2014/12/07/ash-2014-multiple-myeloma-update-day-one-oral-sessions/#Oprozomib
[30] Imbruvica: https://myelomabeacon.org/tag/imbruvica/
[31] selinexor: https://myelomabeacon.org/tag/selinexor/
[32] abstract: https://ash.confex.com/ash/2014/webprogram/Paper67777.html
[33] slide deck: https://myelomabeacon.org/docs/ash2014/31.pdf
[34] Beacon: https://myelomabeacon.org/news/2014/12/07/ash-2014-multiple-myeloma-update-day-one-oral-sessions/#Imbruvica
[35] abstract: https://ash.confex.com/ash/2014/webprogram/Paper75658.html
[36] Ricolinostat: https://myelomabeacon.org/tag/ricolinostat/
[37] abstract: https://ash.confex.com/ash/2014/webprogram/Paper72641.html
[38] abstract: https://ash.confex.com/ash/2014/webprogram/Paper75422.html
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