American Society of Hematology 2016: Multiple Myeloma Highlights

February 2017 Vol 10, Special Issue: Payers’ Perspectives In Oncology: ASH 2016 Highlights - Multiple Myeloma

In This Article


Adding Daratumumab to Lenalidomide and Dexamethasone in Previously Treated Patients with Relapsed or Refractory Multiple Myeloma Improves Outcomes

Daratumumab demonstrated superior efficacy when combined with lenalidomide plus dexamethasone compared with lenalidomide and dexamethasone alone in a prespecified interim analysis of a randomized phase 3 clinical trial of patients with relapsed or refractory multiple myeloma. In the subgroup analyses of the POLLUX study, Usmani and colleagues evaluated outcomes in patients who received 1 to 3 previous lines of therapy, including outcomes based on high-risk cytogenetic therapy.

The patients were randomized to receive lenalidomide and dexamethasone with daratumumab (N = 286) or without daratumumab (N = 283). Patients with high-risk cytogenetic status had ≥1 abnormalities, including t(4;14), t(14;16), or del17p. The median age was 65 years in both arms, and other clinical characteristics were similar.

At 18 months of follow-up, the median progression-free survival (PFS) was not reached in the group that received the combination with daratum­umab compared with 17.5 months in the group that received lenalidomide and dexamethasone alone (P <.0001). The estimated 18-month PFS rates were 76% and 49%, respectively.

In the subgroup of patients with high-risk cytogenetics, median PFS was not reached with the 3-drug combination arm versus 10.2 months with lenalidomide and dexamethasone alone (P = .475). Among patients who received 1 to 3 previous lines of therapy whose disease was refractory to the last line of therapy, the median PFS at 18 months was significantly prolonged with the 3-drug regimen versus the 2-drug regimen with lenalidomide and dexamethasone (not reached vs 10.3 months). Furthermore, the data showed that responses deepened over time for patients receiving the 3-drug regimen. At 18 months, the overall response rate was 87% in the 3-drug combination arm versus 64% in the 2-drug arm; approximately 31.5% of these were stringent complete responses.

Patients who received the dara­tumumab combination therapy also showed better minimal residual disease (MRD)-negativity rates compared with those receiving lenalidomide and dexamethasone alone. At a sensitivity threshold of 10-4, 31.6% versus 8.8% of patients achieved MRD-negativity with daratumumab combination therapy versus lenalidomide and dexamethasone alone, respectively.

The investigators concluded that the deep and durable responses associated with daratumumab when added to lenalidomide and dexamethasone translated into significantly improved clinical outcomes in this patient population.

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Real-World Evidence Regarding Newer Treatment Options, Overall Survival, and Healthcare Costs in Patients with Multiple Myeloma

Limited real-world evidence is available to describe the recent trends in multiple myeloma (MM) treatment costs and outcomes. This study assessed trends in novel therapy use, total healthcare costs, and survival outcomes among patients with newly diagnosed MM in the United States since 2000. Novel agents approved for use in 2015 were not included in the analysis.

Patients aged ≥18 years with 2 or more medical claims with MM between January 2000 and September 2015 were identified in administrative claims databases. The first medical claim for MM was the index date. Controls were selected from a pool of patients without MM and matched 1:1 with MM patients on index year, age, sex, and geographic region. Total healthcare costs were defined as the sum of health plan– and patient-paid costs for inpatient admissions, outpatient services, and outpatient prescriptions. MM treatment-related drug costs included outpatient prescription costs and infusion costs from medical services associated with MM treatment.

After exclusions, 18,260 patients were matched to controls. The proportion of patients with MM using newer therapies (ie, pomalidomide, carfilzomib, bortezomib, lenalidomide, or thalidomide) continuously increased—from 8.7% in 2000 to 61.3% in 2014. The total per-patient per-month all-cause healthcare costs increased from $3263 in 2000 to $14,656 in 2014 in newly diagnosed patients; these increases were primarily driven by costs of outpatient services. Hospitalization costs accounted for 21.5% of the total costs in 2000, which increased to 32.7% in 2014. Treatment-related drug costs for MM accounted for 10.6% of the total costs in 2000, 23.6% in 2009, and 28.5% in 2014.

Patients diagnosed with MM after 2010 had significantly higher utilization rates of newer drugs and significantly better survival outcomes than patients diagnosed before 2010. In fact, patients diagnosed in 2012 were 1.25 times more likely to survive 2 years than those diagnosed in 2006. Overall survival outcomes improved over the study period, with the 2-year survival gap between patients with MM and their matched controls decreasing at an annual rate of 3%.

These findings are aligned with clinical data, suggesting that the increase in novel MM treatment options over the past 15 years has led to substantial survival gains. Although total healthcare costs among patients with newly diagnosed MM have increased steadily since 2000 because of increases in all healthcare cost categories, the contribution of drug costs has remained stable since 2009 despite new novel therapies coming to market.

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Long-Term Analysis of the CASTOR Trial: Adding Daratumumab to Bortezomib and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile when used in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma.

Investigators of the CASTOR trial examined patient subgroups to compare the efficacy of adding daratumu­mab to bortezomib plus dexamethasone in bortezomib-naive and bortezomib-experienced patient populations. The investigators also evaluated the efficacy of the combination of daratum­umab plus bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with disease refractory to lenalidomide as their last previous line of therapy.

The median follow-up was 13 months, which is the longest period for this treatment regimen.

The subgroup analysis showed the following outcomes:

Bortezomib-naïve patients (N = 172)
The median progression-free survival (PFS) was not reached when adding daratumumab to bortezomib plus dexamethasone, and was 7.5 months with bortezomib and dexamethasone alone; the estimated 12-month PFS rates were 74.6% and 32.3%, respectively.
Bortezomib-exposed patients (N = 326)
The median PFS was 12.4 months when adding daratumumab to the 2 drugs versus 6.7 months with bortezomib and dexamethasone alone; the estimated 12-month PFS rates were 51.3% and 15.2%, respectively.
Lenalidomide-refractory patients (N = 105)
The median PFS was 9.3 months with daratumumab added to the 2 drugs versus 4.4 months with bortezomib and dexamethasone alone.

The objective response rates, including very good partial response or better, improved significantly when adding daratumumab to bortezomib and dexamethasone in all subsets of patients with multiple myeloma.

According to the investigators, these subset analyses confirm that the addition of daratumumab to the combination of bortezomib and dexamethasone significantly improves outcomes for patients with relapsed or refractory multiple myeloma, regardless of whether or not they received previous treatment with bortezomib.

In addition, the benefit of adding daratumumab to bortezomib and dexamethasone versus bortezomib and dexamethasone alone was maintained in patients with disease refractory to lenalidomide as their last previous line of therapy.

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The Use of Early Response Can Guide Treatment Selection in Patients with Newly Diagnosed Multiple Myeloma

In 2015, the combination of bortez­omib, lenalidomide, and dexamethasone was shown to improve survival outcomes versus lenalidomide and dexamethasone alone in patients with newly diagnosed multiple myeloma. However, this triplet therapy also increased patients’ risk for severe peripheral neuropathy.

Because no test is available to guide the choice of treatment, the Cleveland Clinic designed a response-based treatment pathway, or “carepath,” that tailors therapy according to early response end points as well as patients’ ability to pay for treatment.

In the carepath, newly diagnosed patients with symptomatic, measurable multiple myeloma are advised to begin a 2-drug regimen of lenalidomide and dexamethasone. If cast nephropathy is suspected or the lenalidomide copay is too high, treatment with bortezomib and dexamethasone would begin.

Depending on patient response, treatment intensity can be increased with the sequential addition of lenalidomide or bortezomib, or cyclophosphamide followed by liposomal doxorubicin when the patient has an inadequate response to the first regimen.

Once patients achieve partial responses, they are evaluated for autologous stem-cell transplantation or consolidation with their induction regimen followed by lenalidomide or bortezomib maintenance.

Over a 3-month period, the carepath was used in 91 patients; of these, 23 (28.4%) patients had high-risk cytogenetics and 33 (36%) had International Staging System stage III. During the study, 54% of patients remained using a doublet therapy.

At a median follow-up of 20.5 months, 84 (92%) patients achieved at least a partial response, 63 (69%) achieved at least very good partial remission, and 6 (7%) achieved complete remission documented by bone marrow exam.

The researchers concluded that early data support the implementation of this response-adapted strategy for newly diagnosed patients with multiple myeloma. This approach achieved disease control comparable to the new standard triplet regimen bortezomib, lenalidomide, and dexamethasone but requires only 2 drugs in half the patients.

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Using Montelukast to Reduce Infusion Reactions in Patients with Relapsed or Refractory Multiple Myeloma

Daratumumab therapy is successful in patients with multiple myeloma who have received ≥3 previous lines of therapy, including a proteasome inhibitor and an immunomodulatory drug (IMid), or whose disease is double-refractory to those other drugs. However, daratumumab has led to infusion-related reactions in clinical trials, including symptoms (eg, cough, wheezing, rhinorrhea) that are associated with allergic rhinitis. Anecdotal reports indicate that premedication with montelukast, a leukotriene receptor antagonist, may reduce the rate of infusion-related reaction associated with daratumumab therapy.

Investigators used a multicenter, open-label treatment protocol to provide early access to daratumumab and to collect safety data, including infusion-related reactions. In this study, 60 patients received montelukast during multiple myeloma therapy, including 50 patients who received montelukast 10 mg >30 minutes before the first infusion of daratumumab. Infusion-related reactions at first infusion were 38.0% with montelukast and 58.5% without it.

Respiratory symptoms (20% vs 12%) and gastrointestinal symptoms (11% vs 4%) were observed in more patients who did not receive montelukast compared with those who did, respectively. Chills were seen in 14% of patients in each group.

The median time to infusion was 6.7 hours for patients who received montelukast compared with 7.6 hours for those who did not. Times for the second and subsequent infusions were similar in both groups.

According to the investigators, these findings show that administering montelukast >30 minutes before the first infusion with daratumumab reduced the rate of infusion-related reactions by approximately 33% in patients who had received >3 previous therapies, including a proteasome inhibitor and an IMid, or whose disease was double-refractory to those agents. The median time for the first infusion was 0.9 hours shorter in patients who received montelukast.

Although the findings from this small-scale observational study are promising, the authors acknowledge that additional studies are required to determine whether montelukast mitigates infusion-related reactions associated with the first infusion of daratumumab.

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Last modified: February 21, 2017
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