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 56^th 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.

1. The revised IMWG criteria for the diag­nosis of mul­ti­ple myeloma now in­clude all of the fol­low­ing “myeloma-defining events” except:
1. The presence of 60 per­cent plasma cells in the bone mar­row
2. Doubling of the mono­clonal pro­tein (M-spike) in less than three months
3. More than one focal lesion on MRI scan
4. An in­volve­d/uninvolved serum free light chain ratio of 100

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, re­lated Beacon 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:

1. Clonal bone mar­row plasma cell per­cent­age greater than 60 per­cent
2. Involved to un­in­volve­d serum free light chain ratio greater than or equal to 100 (the in­volve­d free light chain must be greater than or equal to 100 mg/L)
3. More than one focal lesion on MRI stud­ies, with each being at least 5 mm or more in size.

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.

2. Which of the fol­low­ing state­ments re­gard­ing the ASPIRE trial is true:
1. Patients treated with Kyprolis (car­filz­o­mib), Revlimid (lena­lido­mide), and dexa­meth­asone (Deca­dron) had im­proved over­all sur­vival com­pared to those treated with Revlimid and dexa­metha­sone
2. Patients treated with Kyprolis, Revlimid, and dexa­metha­sone ex­peri­enced higher rates of heart-related side effects com­pared to those treated with Revlimid and dexa­metha­sone
3. Patients treated with Kyprolis, Revlimid, and dexa­metha­sone ex­peri­enced higher rates of kidney toxicity com­pared to those treated with Revlimid and dexa­metha­sone
4. Patients treated with Kyprolis, Revlimid, and dexa­metha­sone ex­peri­enced an im­prove­ment in their quality of life com­pared to those treated with Revlimid and dexa­metha­sone.

Correct answer: .

The ASPIRE trial was a ran­domized, open-label, multi­center Phase 3 study of Kyprolis, Revlimid, and dexa­metha­sone versus Revlimid and dexa­metha­sone in patients with re­lapsed mul­ti­ple myeloma (ASH abstract, slide deck, re­lated journal article abstract, re­lated Beacon news).

The pri­mary end point – pro­gres­sion-free sur­vival – was statistically superior for Kyprolis, Revlimid, and dexa­metha­sone (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.

3. Which of the fol­low­ing state­ments about mono­clonal anti­body ther­a­pies in devel­op­ment for myeloma is true:
1. Elotuzumab is a mono­clonal anti­body targeted to SLAM7
2. The target for elotuzumab is pro­duced only by plasma cells
3. Daratumumab and SAR650984 are mono­clonal anti­bodies targeted to the CD138 an­ti­gen
4. Daratumumab, SAR650984, and elotuzumab are directly toxic to myeloma cells.

Correct answer: .

Elotuzumab, 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). 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 and SAR650984 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, slide deck, re­lated Beacon 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 (bor­tez­o­mib), 40 per­cent of patients re­frac­tory to Kyprolis, and 33 per­cent of patients re­frac­tory to Pomalyst (poma­lido­mide, Imnovid) (abstract, slide deck, re­lated Beacon news).

4. Which of the fol­low­ing state­ments about novel drugs in devel­op­ment for myeloma with re­­sults pre­sented at the ASH 2014 annual meeting is correct:
1. Ixazomib (MLN9708) and oprozomib are oral pro­te­a­some in­hib­i­tors cur­rently in Phase 3 stud­ies for mul­ti­ple myeloma
2. Selinexor is a novel oral sel­ective histone deacetylase (HDAC) in­hib­i­tor
3. Imbruvica (ibrutinib) is an in­hib­i­tor of bruton’s tyrosine kinase (BTK)
4. Ricolinostat (ACY-1215) showed robust single-agent ac­­tiv­ity in mul­ti­ple myeloma.

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 and oprozomib 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, slide deck, re­lated Beacon 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, slide deck, re­lated Beacon news).

Also at the ASH 2014 meeting, data were pre­sented on Imbruvica, a Bruton’s tyrosine kinase in­hib­i­tor, and selinexor, 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, slide deck, re­lated Beacon 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).

Ricolinostat (ACY-1215) is an oral sel­ective histone deacetylase 6 in­hib­i­tor. At the ASH 2014 meeting, ricolinostat in com­bi­na­tion with Velcade and dexa­metha­sone (abstract), and in com­bi­na­tion with Revlimid and dexa­metha­sone (abstract), 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.