Combination of Carfilzomib, Pomalidomide, and Dexamethasone Well Tolerated in Patients with Relapsed/Refractory Multiple Myeloma

Combination therapies for patients with relapsed and/or refractory forms of multiple myeloma (MM) continue to expand with a number of recent drug approvals, including the proteasome inhibitor carfilzomib.

In a recent phase I, open-label, multicenter, dose-escalation trial, Jatin J. Shah, MD, and colleagues examined the safety of a three-drug combination of carfilzomib and pomalidomide together with dexamethasone (CPD) in patients with relapsed and/or refractory MM, and found that the combination was well tolerated in this population.

“When patients become refractory to lenalidomide and bortezomib, unfortunately, the survival is rather short,” Dr. Shah told ASH Clinical News. “This combination is very well tolerated without any neuropathy or significant toxicity, and is also highly active in the most difficult-to-treat disease, such as patients with high-risk [MM].”

Dr. Shah and colleagues enrolled 32 adult patients in the trial. Patients were included if they had a confirmed diagnosis of MM that
was relapsed after prior therapy or that was refractory to the most recently received therapy.

Patients also must have received prior lenalidomide therapy and have been refractory to a regimen containing a full 25 mg or maximum tolerated dose (MTD) of lenalidomide. Additional study inclusion criteria included: Eastern Cooperative Oncology Group score of 0 to 2, adequate hepatic function, and adequate bone marrow function.

Patients were excluded from the study if they had congestive heart failure, symptomatic ischemia, conduction system abnormalities uncontrolled by conventional intervention, myocardial infarction in the previous six months or uncontrolled hypertension, or significant neuropathy.

The study’s primary endpoint was identifying the MTD. Secondary endpoints included the preliminary efficacy of CPD in terms of overall response rate (ORR), complete response rate, very good partial response (VGPR) rate, partial response rate (PRR), minimal response rate (MRR), time to progression, progression-free survival (PFS), and overall survival (OS).

Per treatment protocol, all patients received:

  • Carfilzomib intravenously over 30 minutes on days 1, 2, 8, 9, 15, and 16 every 28 days for the first six cycles, with a starting dose of 20/27 mg/m2
  • Pomalidomide orally once daily on days 1 through 21 every 28 days, with a 4 mg initial starting dose
  • Dexamethasone 40 mg delivered orally or intravenously on a weekly basis on days 1, 8, 15, and 22 of 28-day cycles

After the first four cycles, it was recommended that the dexamethasone dose be reduced to 20 mg. After six cycles of treatment, patients could continue on maintenance therapy as long as, in the eyes of the investigator, they were deriving clinical benefit from the drugs.

All patients were evaluated for hematologic and non-hematologic dose-limiting toxicities.

Of the 32 patients included in the study, 28 patients had an  adverse event related to the study treatment or an infection: 63 percent of patients (n=20) had a grade 3 event, 31 percent (n=10) had a grade 4 event, and 6 percent of patients (n=2) had fatal events of pneumonia and pulmonary embolism (TABLE 1). Five patients (16%) received platelets transfusions, and 19 patients (59%) required at least one transfusion of red blood cells (median = 1; range 0-13).

“Treatment-emergent peripheral neuropathy was uncommon, with six patients experiencing grade 1 peripheral neuropathy and one patient experiencing grade 2 peripheral neuropathy,” the authors noted. Additional reported hematologic and non-hematologic toxicities can be found in TABLE 1.

Eight patients had dose reductions during therapy, and seven patients discontinued treatment due to adverse events. Patients received a median of seven treatment cycles.

In terms of the secondary endpoints, the ORR was 50 percent among the study patients, with:

  • 16% of patients achieving VGPR
  • 34% achieving PRR
  • 16% achieving MRR
  • 25% with stable disease

An analysis of response rate according to MM subtype is provided in TABLE 2.

After a median follow-up of 26.3 months (range = 1-37 months), the median PFS was 7.2 months (95% CI 3-9) and median OS was 20.6 months (95% CI 11.9-28.7), with a 12-month OS rate of 67 percent.

“[CPD] is quickly becoming a standard-of-care option for patients with lenalidomide-refractory myeloma, with response rates and survival superior to either drug alone,” Dr. Shah said, however there were limitations with this study. For instance, grade 3 rashes occurred, which limited the researchers’ ability to escalate the dose, and, as a result, the MTD may have been underestimated. Additionally, the number of patients included in the study was limited.

The researchers suggested that in future studies, a subsequent dose escalation is conducted in less heavily pretreated patients to reevaluate the MTD of this treatment combination.


Reference

Shah JJ, Stadtmauer EA, Abonour R, et al. Carfilzomib, pomalidomide, and dexamethasone (CPD) in patients with relapsed and/or refractory multiple myeloma. Blood. 2015 September 4. [Epub ahead of print]

TABLE 1. Adverse Events, by Maximum Grade Reported
 

Grade

Total (N=32)
1 2 3 4

5

Hematologic adverse events, n
Anemia

0

4 5 1 0

10

Thrombocytopenia

0

3 4 3 0

10

Neutropenia

0

4 10 4 0 18

Febrile neutropenia

0 0 2 0 0

2

Non-hematologic adverse events, n
Diarrhea

4

1 0 0 0

5

Constipation

6

0 0 0 0

6

Nausea

1

1 1 0 0 3
Emesis

0

1 1 0 0 2

Fatigue

5 9 1 0 0

15

Dyspnea

8 2 1 0 0

11

Rash

4

0 1 0 0

5

Neuropathy/paresthesia

6

1 0 0 0

7

Congestive heart failure

0

0 1 0 0 1

Muscle spasms

4 2 0 0 0

6

Transient ischemic attack

0

0 1 0 0

1

Pulmonary emboli

0

0 1 0 1 2

Deep vein thrombosis

0 1 0 0 0

1

Creatinine elevation

5

4 1 2 0 12

Pneumonia

0 0 3 0 1

4

TABLE 2. Response Rate in All Intent-to-Treat Patients and by Cytogenetic Abnormalities

Response Rate

All evaluable patients (n=32) Hyperdiploid (n=10) Del(13) (n=9)

Del(17p) (n=5)

Overall response rate

16

(50%)

5

(50%)

1

(11%)

4

(80%)

Very good partial response

6

(16%)

1

(10%)

1

(11%

1

(20%)

Partial response

11

(34%)

4

(40%)

0

3

(60%)

Minimal response

5

(16%)

3

(30%)

3

(33%)

0

Stable disease

8

(25%)

2

(20%)

5

(56%)

1

(20%)

Progressive disease

3

(9%)

0 0

0

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