A happy Tuesday to you, myeloma world.

We have some in­ter­est­ing re­search to share with you.

First, we have re­­sults of a Phase 2 study investi­gating Empliciti (elotuzu­mab) in com­bi­na­tion with Velcade (bor­tez­o­mib) and dexa­metha­sone (Decadron) in re­lapsed and re­frac­tory myeloma patients. The re­­sults show that Empliciti plus Velcade and dexa­metha­sone im­proves pro­gres­sion-free sur­vival com­pared to Velcade and dexa­metha­sone alone, without adding any sig­nif­i­cant side effects.

We also report on a study out of Italy that explores using Treanda (benda­mustine) in addi­tion to mel­phalan (Alkeran) as the high-dose chemo­therapy used during stem cell trans­planta­tion. The study authors found that using the two drugs to­geth­er is feasible and the combi­na­tion appears to be asso­ci­ated with fewer side effects than mel­phalan alone.

Empliciti In Com­bi­na­tion With Velcade And Dexa­meth­a­sone

An inter­na­tional team of myeloma re­searchers has pub­lished re­­sults of a Phase 2 trial investigating Empliciti in com­bi­na­tion with Velcade and dexa­meth­a­sone in re­lapsed and re­frac­tory myeloma patients (abstract).

The recently pub­lished re­­sults are similar to those pre­sented last De­cem­ber at the 2016 American Society of He­ma­tol­ogy (ASH) meeting (abstract).

The re­­sults are notable because Empliciti's approved use in the United States is in com­bi­na­tion with Revlimid (lena­lido­mide) and dexa­meth­a­sone – rather than Velcade and dexa­meth­a­sone – in mul­ti­ple myeloma patients who have re­ceived one to three prior ther­a­pies (see re­lated Beacon news). Also, Empliciti is ex­pected to re­ceive a similar ap­prov­al in Europe (see re­lated press re­lease).

Dr. Ruben Niesvizky, a myeloma spe­cialist at Weill-Cornell Medicine in New York City who was not in­volved in the Empliciti study, told The Beacon that the new study sug­gests the com­bi­na­tion of Empliciti, Velcade, and dexa­meth­a­sone is "safe and ef­fec­tive in re­lapsed and re­frac­tory myeloma and provides en­cour­ag­ing pro­gres­sion-free sur­vival." (For extended feedback from Dr. Niesvizky about the study, see fur­ther below, near the end of this article.)

The Empliciti, Velcade, and dexa­meth­a­sone Phase 2 study in­cluded 152 re­lapsed and re­frac­tory myeloma patients. To par­tic­i­pate in the trial, patients had to have re­ceived one to three prior lines of ther­apy. Prior treat­ment with Velcade or another drug from the pro­te­a­some in­hib­i­tor class of treat­ments, which in­cludes Velcade and Kyprolis (car­filz­o­mib), was permitted, and about half the trial par­tic­i­pants were pre­vi­ously treated with a pro­te­a­some in­hib­i­tor.

Trial par­tic­i­pants were ran­domly assigned to re­ceive treat­ment with either Empliciti plus Velcade and dexa­metha­sone, or just Velcade and dexa­metha­sone.

Overall re­sponse rates were similar across the two treat­ment groups – 66 per­cent for patients re­ceiv­ing Empliciti plus Velcade and dexa­metha­sone, versus 63 per­cent in patients re­ceiv­ing Velcade and dexa­meth­a­sone. However, patients re­ceiv­ing Empliciti plus Velcade and dexa­metha­sone achieved deeper re­sponses; 36 per­cent of patients re­ceiv­ing Empliciti plus Velcade and dexa­metha­sone achieved a very good partial re­sponse (VGPR) or better, com­pared to 27 per­cent of patients re­ceiv­ing Velcade and dexa­metha­sone.

Median pro­gres­sion-free sur­vival (PFS) was longer for patients re­ceiv­ing Empliciti plus Velcade and dexa­metha­sone (9.7 months) than for patients re­ceiv­ing Velcade and dexa­metha­sone (6.9 months).

Early over­all sur­vival data in­di­cate that the Empliciti com­bi­na­tion provides a sur­vival ben­e­fit. The two-year over­all sur­vival was 73 per­cent for patients re­ceiv­ing Empliciti plus Velcade and dexa­metha­sone and 66 per­cent for patients re­ceiv­ing Velcade and dexa­metha­sone. However, the re­searchers point out that no conclusions can be drawn at this time due to the lim­ited num­ber of events, and that follow-up con­tinues.

Patients re­ceiv­ing the Empliciti com­bi­na­tion ex­peri­enced slightly higher rates of severe side effects (71 per­cent versus 60 per­cent for patients re­ceiv­ing Velcade-dexa­metha­sone). However, the study authors note that they did not observe any addi­tional clin­i­cally sig­nif­i­cant side effects with the Empliciti com­bi­na­tion com­pared to Velcade-dexa­metha­sone alone.

The most common severe side effects in­cluded in­fec­tions (21 per­cent versus 13 per­cent) and low platelet counts (9 per­cent versus 17 per­cent). The re­searchers mention that the rate of in­fusion reac­tion, a side effect often seen with mono­clonal anti­body ther­apy, was low (5 per­cent) and man­ageable with premedication.

The study authors also found that patients with a par­tic­u­lar ge­netic char­ac­ter­istic had noticeably longer pro­gres­sion-free sur­vival when treated with the Emplicit regi­men than patients who did not have that char­ac­ter­istic. Among the patients treated with Empliciti, Velcade, and dexa­meth­a­sone, those with the V/V form of the FCGR3A gene had pro­gres­sion-free sur­vival of 22.3 months, while those with the F/F form of the gene had pro­gres­sion-free sur­vival of 9.8 months.

“Taking into account all lim­i­ta­tions of cross-study comparisons,” the re­searchers write, “it appears that the pro­gres­sion-free sur­vival, over­all re­sponse rate, and duration of re­sponse re­­sults in the ex­per­i­men­tal and con­trol arms seen in the cur­rent study are similar to those reported in other stud­ies that eval­u­ated triple com­bi­na­tions with [Velcade-dexamethasone], sug­gesting that the addi­tion of elotuzumab to [Velcade-dexamethasone] provides similar ben­e­fit than addi­tion of another alter­na­tive third agent to [Velcade-dexamethasone]. Addi­tionally, the re­­sults obtained with EBd appear to sug­gest that addi­tion of elotuzumab to [Velcade-dexamethasone] provides similar rel­a­tive ben­e­fits as the addi­tion of elotuzumab to lena­lido­mide and dexa­meth­a­sone.”

The re­searchers conclude that “Based on re­­sults from this Phase 2 study, fur­ther in­ves­ti­ga­tion of elotuzumab with a pro­te­a­some in­hib­i­tor in re­lapsed / refractory myeloma is warranted.”

Treanda Plus Melphalan As Conditioning Regimen For Second Transplant

Our sec­ond study to­day is a small, single-arm Phase 2 trial con­ducted in Italy. The Italian re­searchers in­ves­ti­gated the use of Treanda (bendamustine) in com­bi­na­tion with mel­phalan (Alkeran) as con­di­tioning regi­men for stem cell trans­plan­ta­tion in newly diag­nosed myeloma patients (abstract).

In par­tic­u­lar, the re­searchers used the com­bi­na­tion as part of the con­di­tioning treat­ment (high-dose chemo­ther­apy) used during the sec­ond trans­plant in a tandem (back-to-back) trans­plant ap­proach in effort to find the best con­di­tioning regi­men for stem cell trans­plan­ta­tion.

Treanda, which already is approved by the U.S. Food and Drug Admin­istra­tion for the treat­ment of chronic lym­pho­cytic leukemia and cer­tain lym­phomas, has been in­ves­ti­gated in a num­ber of stud­ies as treat­ment for mul­ti­ple myeloma.  It is in the class of drugs known as al­kyl­at­ing agents, which also in­cludes mel­phalan and cyclo­phos­pha­mide (Cytoxan). According to the Italian re­searchers, Treanda has ac­­tiv­ity in multi-resistant cell lines that do not respond to treat­ment with other al­kyl­at­ing agents.

The study in­cluded 32 newly diag­nosed myeloma patients who were scheduled to re­ceive tandem trans­plants. All patients had re­ceived a Velcade-based induction ther­apy (in com­bi­na­tion with corticosteroids with or without thalido­mide).

For the first trans­plant, the patients re­ceived high-dose mel­phalan (200 mg/m²) as con­di­tioning ther­apy. Three to six month fol­low­ing their first trans­plant, patients who had achieved at least stable dis­ease underwent a sec­ond trans­plant with Treanda (200 mg/m²) and mel­phalan (140 mg/m²) as con­di­tioning regi­mens.

Neutrophil engraftment oc­curred within a median of 11 days and and platelet engraftment within a median of 12 days after the sec­ond trans­plant. The median duration of hospi­tal­iza­tion after the sec­ond trans­plant was 16 days. The re­searchers point out that engraftment and re­cov­ery after the sec­ond trans­plant was basically the same as after the first trans­plant

Overall, 81 per­cent of patients responded to the first trans­plant and 91 per­cent to the sec­ond, with 47 per­cent of patients achieving a com­plete re­sponse after the first trans­plant and 63 per­cent after the sec­ond.

At a median follow-up time of 16 months after the sec­ond trans­plant, the median pro­gres­sion-free and over­all sur­vival were not reached. The two-year pro­gres­sion-free sur­vival and over­all sur­vival were 79 per­cent and 97 per­cent, re­spec­tively.

The patients ex­peri­enced the usual trans­plant-related side effects of vomiting, diarrhea, and mucositis (an inflammation and ulceration of the mucous membranes lining the digestive tract). However, the re­searchers point out that the rates of mucositis and vomiting were sig­nif­i­cantly lower with the Treanda plus mel­phalan regi­men than with mel­phalan only (83 per­cent versus 97 per­cent for mucositis, and 78 per­cent versus 100 per­cent for vomiting).

Based on their findings, the Italian re­searchers conclude that Treanda plus mel­phalan is feasible as a con­di­tioning regi­men for sec­ond trans­plant in mul­ti­ple myeloma patients. They add that their study may pave the way for Phase 3 stud­ies fur­ther investigating this com­bi­na­tion strat­e­gy. They also rec­om­mend that this com­bi­na­tion be in­ves­ti­gated fur­ther as a con­di­tioning regi­men in a first or single trans­plant setting.

More From Dr. Niesvizky On The Empliciti-Velcade-Dexamethasone Results

Myeloma spe­cialist Dr. Ruben Niesvizky of Weill-Cornell Medicine shared extensive feedback with The Beacon about the Empliciti, Velcade, and dexa­meth­a­sone study re­­sults discussed earlier in this article. We in­clude here, with Dr. Niesvizky's permission, the entire text of his feedback.

Please note that, in his feedback, Dr. Niesvizky refers to Empliciti and Velcade by their generic names, elotuzumab and bor­tez­o­mib (respectively).

Dr. Jakubowiak and his co-authors present very provocative data from a pilot ran­dom­ized Phase 2 study. The protocol explores the safety and ef­fi­cacy of the com­bi­na­tion of elotuzumab, bor­tez­o­mib, and dexa­meth­a­sone (Ebd) in comparison to bor­tez­o­mib and dexa­meth­a­sone (Bd) as con­trol in the treat­ment of re­lapsed and re­frac­tory myeloma patients. The study also has some im­por­tant correlative exploratory analyses.

For a ran­dom­ized Phase 2 study, the methodology and statistics are sound and well run. Unfortunately, no risk data is avail­able in more than 50% in each arm, and there­fore any analysis of effects on risk can’t be per­formed.  Also, the authors state that dose intensity (DI) was well bal­anced and exceeded 90% for elotuzumab, bor­tez­o­mib, and dexa­meth­a­sone. However, a closer look is needed in regard to rel­a­tive DI  with total corticosteroid dose – i.e., in­tended versus given (presented as an I/G ratio).

Even though over­all re­sponses were similar among the groups and there was no dif­fer­ence in sCR/CR [stringent com­plete re­sponse / com­plete re­sponse] among test and con­trol arms, it is in­ter­est­ing that there is a large dif­fer­ence be­tween VGPR rates be­tween the arms, favoring Ebd. This might be a reflection of high anti-tumor ac­­tiv­ity of the Ebd com­bi­na­tion despite po­ten­tial inter­fer­ence with the serum immuno­fix­a­tion caused by the IgG kappa of the anti-SLAMF7 anti­body.

Even in the absence of convincing fa­vor­able re­sponse data, and under the lim­i­ta­tion of Phase 2 stud­ies,  the pro­gres­sion-free sur­vival (PFS) (median and HR) shows a sig­nif­i­cant ben­e­fit in favor of the Ebd arm. Toxicity analyses are en­cour­ag­ing and do not sug­gest any worrisome effect of the com­bi­na­tion.

Very in­ter­est­ing is the correlative stud­ies in regard to Fc(gamma)RIIIa [FCGR3A], in which patients homozygous to the high affinity allele appeared to fare better in regard to pro­gres­sion-free sur­vival than patients homozygous to the low affinity allele. Also in­ter­est­ing are the data pre­sented on the dynamics of NK cells as effectors of elotuzumab ac­­tiv­ity.

We can there­fore conclude that there is now evi­dence that sug­gests the com­bi­na­tion of Ebd is safe and ef­fec­tive in re­lapsed and re­frac­tory myeloma and provides en­cour­ag­ing pro­gres­sion-free sur­vival. What remains to be de­ter­mined are: the real effect on poor risk groups; the true effect of bor­tez­o­mib on NK cells vis-a-vis clin­i­cal out­comes; the value of NK cell quantification; and the deter­mi­na­tion of homozygocity of Fc(gamma)RIIIa V as a bio­marker.

New Myeloma-Related Re­search Articles

1. Jakubowiak, A. et al., “Randomized phase 2 study of elotuzumab plus bortezomib/dexamethasone (Bd) versus Bd for relapsed/refractory multiple myeloma” in Blood, April 18, 2016 (abstract)
2. Lu, Y. et al., “miR-320a regulates cell proliferation and apoptosis in multiple myeloma by targeting pre-B-cell leukemia transcription factor 3” in Biochemical and Biophysical Research Communications, April 14, 2016 (abstract)
3. Martino, M. et al., “A phase II, single-arm, prospective study of bendamustine plus melphalan conditioning for second autologous stem cell transplantation in de novo multiple myeloma patients through a tandem transplant strategy” in Bone Marrow Transplantation, April 18, 2016 (abstract)