Relapsed/refractory patients

Clarithromycin, pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma: results from a phase II study

Elderly patients with relapsed/refractory multiple myeloma (RRMM), often become increasingly frail with each subsequent line of therapy. There is a requirement for effective, well-tolerated treatment strategies for these patients. The efficacy of a pomalidomide and dexamethasone (pom-dex) combination, has been shown in previous studies, with a further additional benefit in overall response rate (ORR) observed when an additional drug is included, such as daratumumab. Adding clarithromycin to regimens used for patients with newly diagnosed MM (NDMM) has also conferred an increased ORR and progression-free survival (PFS).

The evidence above provided the rationale for Tomer M. Mark, University of Colorado Anschutz Medical Campus, Aurora, CO, and colleagues, to undertake a single-institution, single-arm, open-label, phase II study (NCT01159574) investigating the all-oral combination of clarithromycin, pomalidomide and dexamethasone (ClaPd) in patients with RRMM. It was conducted at the Weill Cornell Medical College/NewYork-Presbyterian Hospital.

Patient Population and study design
  • Adult patients (N = 120)
  • Histologically confirmed MM, refractory to most recent therapy, and refractory/resistant/relapsed to lenalidomide
  • Median prior lines of therapy: 5 (3–15)
    • Lenalidomide- vs bortezomib- vs double-refractory: 84% vs 78% vs 68%
  • High-risk cytogenetics (defined as the presence of del(17p), t(4;14) or t(14;16)): 35%
  • Regimen (all administered orally, in a 28-day cycle):
    • Clarithromycin (Biaxin®): 500 mg, twice daily
    • Pomalidomide (CC-4047®): 4 mg on days 1 and 21
    • Dexamethasone (Decadron®): 40 mg on days 1, 8, 15 and 22
    • Prophylactic aspirin (81 mg) was given daily as was trimethoprim-sulfamethoxazole
  • Treatment continued until disease progression or intolerance
  • Primary objective: ORR
  • Secondary objective: PFS and overall survival (OS) including safety and tolerability, time to maximum response, duration of response (DoR) and time to progression or treatment failure
Key Findings

Efficacy (N = 117)

  • Median follow-up: 20.3 months (0.3–92.7)
  • Median time on study: 7.2 months (0.3–57.2)
  • ORR: 60% (n = 70)
  • Very good partial response (VGPR): 23%
  • Median time to partial response: 1 cycle (1–7)
  • Median DoR: 9.3 months
  • Median PFS: 7.7 months (95% CI, 5.6–9.5)
  • Median OS: 19.2 months (95% CI, 14.2–26.7)
  • ORR, PFS and OS were not influenced by lenalidomide or bortezomib refractory status
  • Cytogenetics:
    • Median PFS (standard vs high risk): 5.8 (95% CI, 3.6–8.6) vs 8.4 (95% CI, 5.7–12.1) months, P = 0.0366
    • Median OS (standard vs high risk): 14.2 (95% CI, 8–25.7) vs 25.0 (95% CI, 16.9–31.6) months, P = 0.0237
    • There was a significant association between del(17p) and OS: 12.4 (95% CI, 6.2–16.8) vs 27.1 (95% CI, 16.9–33.2) months, P = 0.0006

Safety (N = 120)

  • Most common hematological toxicities (grade ≥3):
    • Neutropenia: 58%
    • Thrombocytopenia: 31%
    • Anemia: 28%
  • Most common non-hematological toxicities (grade ≥3):
    • Fatigue: 15%
    • Pulmonary infection: 13%
    • Hyperglycemia: 15%
  • Dose reductions:
    • Pomalidomide: 33% (39/120) but no discontinuations due to toxicity
    • Clarithromycin: 5% (6/120) with 34 discontinuations, predominantly for gastrointestinal adverse events (AEs)
    • Dexamethasone: 57% (68/120) with 5 patients discontinuing
  • Grade 5 AE: 1 patient experienced a grade 5 AE caused by a lung infection

This study showed that the ClaPd regimen increased activity in patients with RRMM who have very few alternative treatment options, and this is irrespective of whether the patient is refractory to either lenalidomide, bortezomib or both. This triplet combination has a manageable toxicity profile with low rates of nonhematologic events. The all-oral nature of this triplet is also more convenient for administration in this heavily pre-treated patient population who are often frail or elderly.

Whilst the clinical trials cannot be directly compared, the response rates and toxicity are similar to studies investigating pomalidomide-dexamethasone doublet regimens, as well as triplet regimens. Compared to the pom-dex regimens alone, ClaPd provides a higher ORR and PFS whilst also having comparable ORR and PFS to similar triplet regimens.

ClaPd versus pom-dex regimens:

Trial name

Phase

Drug regimen

ORR

PFS

OS

ClaPd

II

Pom-dex-clarithromycin

60%

7.7 months

19.2 months

MM-003      

III

Pom-dex

31.4%

4.0 months

12.7 months

STRATUS

IIIb

Pom-dex

32.6%

4.6 months

11.9 months

MM-002

I/II

Pom-dex

37.2%

4.2 months

Not listed

IFM-2009-02

II

Pom-dex

34.5%

4.6 months

14.9 months

ClaPd versus triplet regimens:

Trial reference

Phase

Drug regimen

ORR

PFS

NCT01159574

II

Clarithromycin + pom-dex (ClaPd)

60%

7.7 months

NCT01998971

Ib

Daratumumab + pom-dex (DPD)

60%

8.8 months

NCT02654132

II

Elotuzumab-lenalidomide-dex (EloPD)

53%

10.3 months

NCT01464034

I

Carfilzomib + pom-dex (KPD)

50%

7.2 months

NCT01432600

I/II

Cyclophosphamide + pom-dex (CPD)

65%

9.5 months

NCT02119468

I/II

Ixazomib + pom-dex (IPD)

48%

8.6 months

Utilizing clarithromycin in bortezomib triplets may not be as well-tolerated however, as demonstrated by the early discontinuation of a study investigating clarithryomycin with cyclophosphamide, bortezomib and dexamethasone (CyBorD) in patients with NDMM. This was due to gastrointestinal and neurologic AEs in the clarithromycin group. These may have been due to the inhibition of CYP3A4 by clarithromycin, which is the main metabolizer of bortezomib leading to increased toxicity.

References
  1. Mark T.M. et al. Phase 2 study of clarithromycin, pomalidomide, and dexamethasone in relapsed or refractory multiple myeloma. Blood Advances. 2019 Feb 21. DOI: 10.1182/bloodadvances.2018028027
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