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Key Myeloma Takeaways from ASH 2014

Vij, Ravi MD

doi: 10.1097/01.COT.0000461127.31676.f5
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RAVI VIJ, MD

RAVI VIJ, MD

There were dozens of myeloma abstracts at the ASH Annual Meeting focusing on all aspects of the disease, from basic science to clinical trials with conventional therapies, stem cell transplantation, and data on health outcomes research. It is difficult to do justice to the broad gamut of data, but I will attempt to summarize the highlights on conventional therapeutic agents and novel drugs.

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I. Carfilzomib (Kyprolis) Trials

The ASPIRE trial

Stewart et al presented results of the ASPIRE trial, which was a randomized open-labeled multicenter Phase III study of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma (Abstract 79).

The study enrolled patients with multiple myeloma who had had one to three prior treatments. Patients who had progressive disease while on bortezomib were excluded from the study. Also, excluded were patients who had previously been treated with Revlimid and dexamethasone and had disease progression during the first three months of any treatment regimen or at any time if Revlimid and dexamethasone were the most recent treatment.

A total of 396 patients were enrolled on each arm of the study. Approximately two thirds of patients in both arms had had prior exposure to bortezomib and approximately 15 percent were nonresponsive prior to bortezomib. Over half the patients had prior exposure to immunomodulatory drugs, with approximately 20 percent in each arm having had exposure to lenalidomide. About a fifth of patients were refractory to immunomodulatory drugs in a prior regimen in both arms of the study.

The primary endpoint—progression-free survival—was statistically superior for Kyprolis, Revlimid, and dexamethasone (KRd) (26.3 months) compared with use of Revlimid and dexamethasone (Rd) (17.6 months) (HR 0.69, one-sided p value < 0.0001).

A total of 31.8 percent of patients on the KRd arm had a complete response (CR) compared with 9.3 percent of patients on the Rd arm (p < 0.0001). The overall response rates were 87.1 percent and 66.7 percent, respectively (p <0.0001). The progression-free survival (PFS) was superior in patients who had complete response compared with those with lesser levels of response.

With a median follow-up of 32 months, the median overall survival was not reached in either arm (HR 0.79, one-sided p value = 0.018).

Safety analysis showed similar rates of discontinuation due to adverse events (KRd 15.3% versus Rd 17.7%). Other side effects occurred at similar rates in the two arms: dyspnea (KRd 19.4% versus Rd 14.9%), cardiac failure (KRd 6.4% versus Rd 4.1%), ischemic heart disease (KRd 5.9% versus Rd 4.6%), and acute renal failure (KRd 8.4% versus Rd 7.2%). There appeared to be a higher rate of hypertension in the KRd arm (14.3% versus 6.9%). EORTC global health status improved in the KRd group versus the Rd group over 18 cycles of treatment (p=0.0001).

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Carfilzomib cyclophosphamide and dexamethasone

In the setting of newly diagnosed patients with multiple myeloma, Palumbo et al (Abstract 175) conducted a Phase I/II study of carfilzomib given weekly with cyclophosphamide and dexamethasone. The maximally tolerated dose of weekly carfilzomib was 70 mg/m2 with oral cyclophosphamide at a dose of 300 mg/m2 on days 1, 8, and 15 and dexamethasone 40 mg weekly.

Grade 3 adverse events in 30 patients included anemia (10%), neutropenia (10%), and cardiotoxicity (7%). One death due to acute pulmonary edema was considered probably related to treatment.

At the MTD, the overall response rate was 79 percent with a very good partial response rate of 58 percent.

In summary, the ASPIRE trial showed that in the setting of relapsed and refractory disease a triplet regimen of KRd resulted in an impressive PFS advantage over a doublet regimen of Rd. The triplet regimen produced impressive rates of CR with depth response correlating with PFS. The addition of carfilzomib to Revlimid and dexamethasone did not seem to add significantly to the toxicity profile and actually led to a better quality of life during the first 18 cycles of treatment analyzed. Palumbo et al in their trial have incorporated a more convenient regimen of once weekly carfilzomib into a three-drug combination.

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II. Pomalidomide Combinations

Pomalidomide, cyclophosphamide, and dexamethasone

Baz et al (Abstract 303) reported a randomized Phase II study of pomalidomide, cyclophosphamide (PCD), and dexamethasone versus pomalidomide and dexamethasone (PD) in relapsed/refractory multiple myeloma. A total of 70 patients were randomized. Patients in both arms of the study had a median of four prior lines of therapy.

The overall response rate was 64.7 percent for PCD versus 38.9 percent for PD (p=0.03). The median PFS was 9.5 months for PCD versus 4.4 months for PD (p = 0.1078). Grade 3-4 neutropenia was observed in 49 percent of patients in the PCD arm versus 33 percent in the PD arm. Rates of grade 3-4 febrile neutropenia were 17 and 11 percent and thrombocytopenia 13 and five percent, respectively.

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Pomalidomide, bortezomib, and dexamethasone

Lacy et al (Abstract 304) reported on a Phase I/II study of pomalidomide with once-weekly bortezomib and dexamethasone for patients with relapsed lenalidomide refractory multiple myeloma. Patients were allowed to have had one to four prior regimens, and an overall response rate of 85 percent was observed in the 47 patients enrolled. The median progression-free survival was 10.7 months.

In summary, these two trials report on three-drug combination therapies incorporating pomalidomide in the regimen. These add to the list of other three-drug regimens including another regimen incorporating pomalidomide with twice-weekly bortezomib reported earlier by Richardson et al and carfizomib pomalidomide and dexamethasone reported earlier by Shah et al.

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III. Monoclonal Antibodies

Daratumumab, lenalidomide, and dexamethasone

Plesner (Abstract 84) reported a Phase I/II trial of daratumumab (a monoclonal antibody to CD38) with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. Patients had had a median of two prior lines of therapy including bortezomib in 91 percent of patients, immunomodulatory drugs in 80 percent, and a prior autologous stem cell transplant in 73 percent. Patients with disease refractory or intolerant to lenalidomide were excluded from the study.

In the Part I dose-escalation portion of the study, doses were escalated from 2 mg/kg to 16 mg/kg (n=13), and in the Part II expansion cohort patients were treated at 16 mg/kg (n=32).

With a median follow-up of 12.9 months, the overall response rate in Part I of the study was 100 percent, with complete remissions in 31 percent of patients and very good partial responses in 46 percent. With a median follow-up of 5.6 months in Part II of the study, the overall response rate was 86.7 percent with CR in 6.7 percent and very good partial responses in 43 percent. No dose-limiting toxicities were reported.

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SAR650984, lenalidomide, and dexamethasone

Martin et al (Abstract 83) reported on a Phase IB dose-escalation trial of SAR650984 (another anti-CD38 monoclonal antibody) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. In the dose-escalation phase of the study, patients were treated with 3 mg/kg, 5 mg/kg, and 10 mg/kg of SAR650984.

A total of 31 patients were enrolled. Patients had received a median of seven to 10 prior regimens. No MTD was reached, and 18 patients were treated at the dose of 10 mg/kg in an expansion cohort. For 24 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 lenalidomide, 44 percent of patients refractory to bortezomib, 40 percent of patients refractory to carfilzomib, and 33 percent of patients refractory to pomalidomide.

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Elotuzumab, lenalidomide, and dexamethasone

Richardson et al (Abstract 302) reported the final results of the Phase IB/II study of elotuzumab (a monoclonal antibody to SLAM7 or CS1) with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma.

In the Phase II portion of the study, patients were randomized to receive either 10 mg/kg (n=36) or 20 mg/kg (n=37) of elotuzumab. The overall response rate was 92 percent in the 10 mg/kg cohort and 76 percent in the 20 mg/kg cohort. An impressive median PFS of 32.4 months and 25 months, respectively, was reported.

In summary, both monoclonal antibodies to CD38 (daratumumab and SAR650984) and the SLAM7 antibody elotuzumab appear to be well tolerated, with impressive responses when combined with lenalidomide and dexamethasone in patients with relapsed and refractory disease. Elotuzumab in combination with lenalidomide and dexamethasone produced impressive rates of PFS. Results of the ELOQUENT-2 study randomizing patients to elotuzumab (10 mg/kg) with lenalidomide and dexamethasone and lenalidomide and dexamethasone alone are now eagerly awaited.

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IV. Oral proteasome inhibitors

Ixazomib maintenance

Kumar et al (Abstract 82) reported results from a Phase II study of ixazomib maintenance following ixazomib, lenalidomide, and dexamethasone induction in patients with newly diagnosed multiple myeloma. After an initial induction phase of treatment with ixazomib, lenalidomide, and dexamethasone consisting of up to 12 28-day treatment cycles, patients were placed on ixazomib maintenance of 4 mg once weekly on days 1, 8, and 15 of a 28-day cycle. Maintenance was continued until progression or unacceptable toxicity. A total of 65 patients were enrolled, and 25 patients entered the maintenance phase.

The median number of cycles of ixazomib delivered was 31, and the median number of maintenance cycles was 19 (range of 3 to 23).

Ten patients (48%) reported a serious adverse event (SAE) at any time during induction and maintenance treatment, with 19 percent of patients reporting an SAE during the maintenance phase. In total, 81 percent of patients required study drug dose reduction due to an adverse event during induction and 10 percent during the maintenance phase.

A total of 90 percent of patients achieved a partial response or better, with 59 percent having a very good partial response and 22 percent a complete remission after up to 12 cycles of induction. Ixazomib maintenance improved response, with 48 percent of patients showing increased response depth during maintenance.

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Oprozomib

Vij et al (Abstract 34) reported on a Phase IB/II study of single-agent oprozomib in relapsed and refractory multiple myeloma.

Patients were enrolled on two different schedules of the drug on either two out of every seven days or five out of every 14 day-schedule with cycles repeated every two weeks. During the course of the study the oprozomib formulation was changed from a powder and capsule formulation given b.i.d. to an oprozomib tablet given once daily introduced in November 2012. Stepped-up dosing of the drug and an extended-release tablet were introduced in July/August 2014.

A total of 87 patients with multiple myeloma were enrolled. A maximum tolerated dose of the drug was 300 mg/day for the 2/7 schedule and 240 mg/day for the 5/14 schedule.

The major toxicity of the drug was gastrointestinal, with the majority of patients having nausea, vomiting, and diarrhea. The introduction of stepped-up dosing and the extended-release formulation seemed to coincide with improved gastrointestinal tolerability. However, all patients did require mandatory premedication with a 5-HT3 inhibitor and dexamethasone. In addition, the majority of patients required p.r.n. use of antiemetics including NK1 inhibitors and antidiarrheals.

The rates of treatment emergent or worsening peripheral neuropathy were low with only one patient developing greater than grade 3 peripheral neuropathy. Rash was seen in six patients (7%). No grade 3 or higher rash was observed. Two patients died from upper gastrointestinal bleeding on the 5/14 schedule and one patient due to disease progression.

An overall response rate of 31.3 percent on the 2/7 schedule and 23.3 percent on the 5/14 schedule was observed. The overall response rate in 11 carfilzomib refractory patients in the Phase II portion study was 18.2 percent.

In summary, it was demonstrated that ixazomib could be used as maintenance therapy for an extended period of time. This is important as more data emerges supporting the utility of maintenance therapy after both transplant and conventional therapy for patients with multiple myeloma. A Phase III trial of ixazomib with lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in previously untreated multiple is currently enrolling (TOURMALINE-MM2). Also, it appears 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.

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V: The Others

Ibrutinib

Vij et al (Abstract 31) reported a Phase II study of the BTK inhibitor ibrutinib with or without dexamethasone in patients with relapsed and refractory multiple myeloma. A total of 69 patients were enrolled in four cohorts receiving either single-agent ibrutinib or ibrutinib in combination with dexamethasone. Patients had had three to five prior lines of therapy. Three fourths of patients had received steroids in their most recent line of therapy.

The drug was well tolerated, with 25 percent of patients treated on the highest dose level of ibrutinib at 840 mg daily with weekly dexamethasone having a clinical benefit. Median progression-free survival of 5.6 months was observed. The drug was well tolerated with very low rates of grade 3 to 4 toxicity.

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Ricolinostat (ACY-1215)

Vogel et al (Abstract 4764) and Yi et al (Abstract 477) reported Phase I studies of ricolinostat (ACY-1215), an oral selective histone deacetylase 6 inhibitor in combination with bortezomib/dexamethasone (n=43) and lenalidomide/dexamethasone (n=27) in relapsed and refractory multiple myeloma. Toxicities were generally manageable, with overall response rates of 45 percent with ricolinostat, bortezomib, and dexamethasone and 64% with ricolinostat, lenalidomide, and dexamethasone.

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Selinexor

Chen et al (Abstract 4773) reported on a combination of Selinexor (KPT-330), an inhibitor of the nuclear export protein XPO-1, with dexamethasone in patients with heavily pretreated and refractory multiple myeloma. Selinexor at a dose of 45 mg/m2 with dexamethasone 20 mg, both given twice weekly, led to responses in six of nine patients (67%). Adverse events included nausea, vomiting, anorexia, fatigue, and weight loss in a significant proportion of patients.

In summary, preliminary data with ibrutinib, ACY-1215, and selinexor is encouraging and follow-up data from these early trials will be eagerly awaited.

Certainly ASH 2014 reaffirmed that data-set on compounds with activity in multiple myeloma continues to grow. Several new and exciting options are likely to enter our arsenal of clinically available therapies in the near future with the potential of improving further the outcomes of patients with multiple myeloma. Stay tuned!

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Links to Studies

Access the hyperlinks (shown in grey) for all the journal studies noted by reading the article on our iPad app, or by reading the pdf of the article on oncology-times.com.

© 2015 by Lippincott Williams & Wilkins, Inc.
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