General MM

ASH 2018 | Clinical trials for high-risk smoldering multiple myeloma

The 60th American Society of Hematology (ASH) Annual Meeting was held in San Diego, California, from 1–4 December 2018. The content of two oral presentations regarding clinical trials for high-risk smoldering MM (SMM) is outlined below. Both studies were from Irene M. Ghobrial’s group from the Dana-Farber Cancer Institute, Boston, US.

1.

On Saturday 1 December 2018, during an oral abstract session entitled: Myeloma: Therapy, excluding Transplantation: Novel Targeted Combinations in Myeloma, Irene M. Ghobrial presented data from a phase II clinical trial for SMM.1

Recent studies have shown that early treatment of SMM may delay or prevent the progression to MM. This phase II trial uses a triplet regimen of elotuzumab, lenalidomide, and dexamethasone to treat high-risk SMM patients and examines the progression-free survival (PFS) of patients after two years from the time of treatment initiation.

Secondary outcome measures include the response rate, time to disease progression, duration of response, overall survival (OS), and safety of the combination treatment.

Study Design:
  • Period of accrual: January 2015–December 2016
  • Eligibility criteria: As defined by the International Myeloma Working Group (IMWG) updated criteria2
  • Number of enrolled patients = 50
  • Age = 60 years (range, 29–79)
  • Gender = 18 females/32 males
  • Median bone marrow plasma cell involvement = 20%; 20% of patients had the cut off value of 60%
  • Initially, treatment was administered in two arms: Arm A = elotuzumab, lenalidomide, and dexamethasone (40 patients) and arm B = elotuzumab and lenalidomide without dexamethasone (10 patients). However, a high dose of dexamethasone had to be administered during the elotuzumab infusion. For this reason, the non-dexamethasone arm was stopped and all patients were treated as described below.
  • Treatment: 28-day cycles
    • Cycles 1–2: Elotuzumab, 10 mg/kg by intravenous (IV) infusion on days 1, 8, 15, and 22; lenalidomide, 25 mg oral on days 1–21; dexamethasone, 40 mg on days 1, 8, 15, and 22
    • Cycles 3–8: Elotuzumab, 10 mg/kg by intravenous (IV) infusion on days 1 and 15; lenalidomide, 25 mg oral on days 1–21; dexamethasone, 40 mg on days 1, 8, and 15
  • After the 8-cycle treatment, patients were offered the possibility of stem cell collection for a future transplant.
  • After the 8-cycle treatment patients could opt for maintenance therapy for 16 additional cycles (28-day cycles): elotuzumab, 20 mg/kg IV on day 1; lenalidomide, 25 mg oral on days 1–21
Key Data:
  • Number of patients who completed the induction treatment (8 cycles) = 46
  • Number of patients who completed the maintenance treatment (24 cycles) = 40/50
  • Reasons for withdrawing from the study:
    • Missed diagnosis = 3 patients
    • Patient withdrawal = 5 patients
    • Deaths = 2; one death due to diabetic ketoacidosis, bowel perforation and septic shock at cycle 20; another death due to myocardial infarction and uncontrolled hypertension at the end of cycle 24
  • Number of patients who are progression-free at follow-up = 38/40
  • PFS at median follow-up (29 months) = Not reached
  • PFS at 36 months = 95% versus (vs) historical control data of 77% observed with lenalidomide and dexamethasone
  • Response to treatment:
    • Overall response rate (ORR) = 84%
    • Complete response (CR) rate = 6%
    • Very good partial response or better (≥ VGPR) rate = 43%
  • Median time to response = 2.8 months
  • No difference in response between high-risk and standard-risk patients
  • Adverse events (AEs), grade 3/4:
    • Hypophosphatemia = 34% (grade 4, 6%)
    • Neutropenia = 26%
    • Lymphocyte count decrease = 22%
  • The following grade 4 AEs were observed in one patient: Cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia
Conclusions

The elotuzumab, lenalidomide, dexamethasone triplet is well-tolerated in patients with high-risk MM and results in 95% PFS, 36 months after initiation of treatment. Ongoing studies will determine how the immune profile correlates with the response or resistance to treatment.                                          

2.

On Monday 3 December 2018, during an oral abstract session entitled: Myeloma: Therapy, excluding Transplantation: Novel Proteasome Inhibitors, Mark Bustoros presented data from another phase II clinical trial for SMM.3

This phase II trial examined the triplet combination of ixazomib, lenalidomide, and dexamethasone (IRd) for patients with high-risk SMM. The primary outcome of the trial was progression-free survival (PFS) two years after initiation of treatment.

Secondary objectives included assessment of response rate and duration, the safety of the triplet combination, depth of response and minimal residual disease (MRD).

Study Design:
  • Eligibility criteria: As defined by the International Myeloma Working Group (IMWG) updated criteria2
  • Number of enrolled patients = 29
  • Age = 61 years (range, 41–73)
  • Gender = 51.7% male
  • Bone marrow plasma cell involvement = 20% (range, 10–55)
  • Treatment: 28-day cycles
    • Cycles 1–9 (induction): Ixazomib, 4 mg orally on days 1, 8, and 15; lenalidomide, 25 mg orally on days 1–21; dexamethasone, 40 mg orally on days 1, 8, 15, and 22
    • Cycles 10–24 (maintenance): Ixazomib, 4 mg orally on days 1, 8, and 15; lenalidomide, 15 mg orally on days 1–21
Key Data:
  • Median treatment cycles = 14 (range, 3–22)
  • Median follow-up time = 15 months (range, 4.2–22)
  • Number of patients who are progression-free at follow-up = 29/29
  • Response to treatment:
    • ORR = 93.1%
    • CR rate = 27.6%
    • VGPR rate = 24.1%
  • Median time to response = 1.0 month (95% confidence interval [CI], 0.9–1.9)
  • Adverse events (AEs), grade 3:
    • Neutropenia = 1/29 patients (3.4%)
    • Thrombocytopenia = 1/29 patients (3.4%)
    • Hypertension = 2/29 patients (6.8%)
    • Hypophosphatemia = 4/29 patients (13.8%)
    • Rash = 1/29 (3.4%)
  • AEs, grade 4:
    • Neutropenia = 2/29 patients (6.8%)
    • Hyperglycemia = 1/29 (3.4%)
  • Grade 1/2 peripheral neuropathy was observed in 10/29 patients (34.5%) but no cases of grade 3 or 4 were observed
Conclusion

The all-oral triplet combination of ixazomib, lenalidomide, and dexamethasone shows minimal toxicity and high response rates for patients with high-risk SMM, opening an avenue for future studies and longer follow-ups to monitor disease progression.

References
  1. Liu C.J. et al. Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma. 2018 Dec 1; Oral Abstract #154: ASH 60th Annual Meeting and Exposition, San Diego, CA.
  2. Rajkumar S.V. et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014 Nov;15(12):e538-48. DOI: 10.1016/S1470-2045(14)70442-5.
  3. Bustoros M. et al. Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma. 2018 Dec 3; Oral Abstract #804: ASH 60th Annual Meeting and Exposition, San Diego, CA.
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