Elotuzumab for Relapsed or Refractory Multiple Myeloma

Ahroom Youk, Mercer University College of Pharmacy

Multiple myeloma is a plasma cell malignancy that arises from a single precursor tumor stem cell, according to Harrison’s Principles of Internal Medicine.  The authors of this textbook report that new cases of myeloma in the United States were estimated to be 24,050 and deaths due this disease amounted to 11,090 in the year 2014.  They also explain that the resulting effects of this disease is highly unpleasant; patients may experience bone pain, bone fractures, anemia, renal failure, infections, and/or neurologic symptoms.  The authors state that myeloma is typically idiopathic although it occurs more often in farmers, wood and leather workers, and individuals exposed to nuclear radiation or petroleum products.  They suggest that the incidence of this disease increases with age, for the median age at diagnosis is 70 years.  Additionally, possible causes of myeloma they include are chromosomal alterations, such as deletions (13q14 or 17p13), translocations (t(11;14)(q13;32), t(4;14)(p16;q32), or t(14;16)), or hyperdiploidy.  This source also mentions there is strong evidence that errors in switch recombination participate in the process, and that over 40% of patients with myeloma exhibit N-ras, K-ras, or B-raf mutations.1

Elotuzumab is a medication for multiple myeloma that is currently under investigation by Bristol-Myers Squibb Company and AbbVie, Inc., per a press release from Bristol-Myers Squibb.  It describes elotuzumab as a humanized immunoglobulin G1 (IgG1) monoclonal antibody that targets the Signaling Lymphocyte Activation Molecule (SLAMF7 or C1) found on myeloma and Natural Killer cells, but not on normal tissue cells.  These biopharmaceutical companies report that the United States Food and Drug Administration granted elotuzumab (with lenalidomide (Revlimid®) and dexamethasone (Dexamethasone Intensol™, Dexpak®) Breakthrough Therapy Designation for the treatment of multiple myeloma in patients who have received prior therapy.  The press release explains that Breakthrough Therapy Designation expedites the development and review of medications for serious disease states due to promising preliminary clinical evidence.2

“Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma” is a study funded by Bristol-Myers Squibb and AbbVie; the following table summarizes this study.3

Title: Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma3
Design Open-label, multicenter, phase 3, randomized trial; N = 646
Objective To evaluate the efficacy and safety of elotuzumab in combination with lenalidomide and dexamethasone, as compared with lenalidomide and dexamethasone alone, in patients with relapsed or refractory multiple myeloma
Study Groups Elotuzumab plus lenalidomide plus dexamethasone (elotuzumab group); n = 321

Lenalidomide plus dexamethasone (control group); n = 325

Methods All patients received their respective medication regimens in 28-day cycles until withdrawal of consent, disease progression, or unacceptable toxicity.  Patients in the elotuzumab group received premedication prior to the elotuzumab infusion.  During the first two cycles, patients in the elotuzumab group received intravenous (IV) elotuzumab 10 mg/kg on days one, eight, 15, and 22, and on the third cycle they received elotuzumab on days one and 15.  This group additionally received oral lenalidomide 25 mg daily on days one through 21 of each cycle, as well as dexamethasone 40 mg orally on the week without elotuzumab and 8 mg dexamethasone IV plus 28 mg orally on days when elotuzumab was administered.  Patients in the control group received 25 mg lenalidomide orally on days one through 21 and dexamethasone 40 mg orally on days one, eight, 15, and 22.
Duration Enrollment was between June 2011 and November 2012, and median follow-up was 24.5 months.
Primary Outcome Measure Progression-free survival and overall response rate
Baseline Characteristics Characteristic Elotuzumab Group; n = 321 Control Group; n = 325 All Patients; N = 646
Median age, years (range) 67 (37 – 88) 66 (38 – 91) 66 (37 – 91)
Cytogenetic profile, number (%)
     del(17p) 102 (32) 104 (32) 206 (32)
     t(4;14) 30 (9) 31 (10) 61 (9)
Disease stage according to the International Staging System, number (%)
     I 141 (44) 138 (42) 279 (43)
     II 102 (32) 105 (32) 207 (32)
     III 66 (21) 68 (21) 134 (21)
     Not reported 12 (4) 14 (4) 26 (4)
Previous therapy regimens
     Median number (range) 2 (1 – 4) 2 (1 – 4) 2 (1 – 4)
     Regimens, number (%)
          1 151 (47) 159 (49) 310 (48)
          2 118 (37) 114 (35) 232 (36)
          3 or more 52 (16) 52 (16) 104 (16)
Previous stem-cell transplantation, number (%) 167 (52) 185 (57) 352 (54)
Previous therapies, number (%)
     Bortezomib 219 (68) 231 (71) 450 (70)
     Melphalan 220 (69) 197 (61) 417 (65)
     Thalidomide 153 (48) 157 (48) 310 (48)
     Lenalidomide 16 (5) 21 (6) 37 (6)
Results Elotuzumab Group; n = 321 Control Group; n = 325 Hazard Ratio, (95% CI) Odds Ratio, (95% CI)* p-Value Relative Reduction, %**
Progression-free survival, % (95% CI)
     One-year 68 (63 – 73) 57 (51 – 62)
     Two-year 41 (35 – 47) 27 (22 – 33)
Median progression-free survival, months (95% CI) 19.4 (16.6 – 22.2) 14.9 (12.1 – 17.2) 0.70 (0.57 – 0.85) < 0.001 -30
Overall response rate, % (95% CI) 79 (74 – 83) 66 (60 – 71) 1.9 (1.4 – 2.8) < 0.001
* Odds ratio for elotuzumab versus control

** Relative reduction in the risk of disease progression or death

Adverse Events Common Adverse Events
Event Elotuzumab Group; n= 318 Control Group; n= 317
Common hematologic toxic effect, number (%)
     Lymphocytopenia 316 (99) 311 (98)
     Anemia 306 (96) 301 (95)
     Thrombocytopenia 266 (84) 246 (78)
     Neutropenia 260 (82) 281 (89)
Common non-hematologic adverse event, number (%)
     General disorder
          Fatigue 149 (47) 123 (39)
          Pyrexia 119 (37) 78 (25)
          Peripheral edema 82 (26) 70 (22)
          Nasopharyngitis 78 (25) 61 (19)
     Gastrointestinal disorder
          Diarrhea 149 (47) 114 (36)
          Constipation 113 (36) 86 (27)
     Musculoskeletal or connective-tissue disorder
          Muscle spasms 95 (30) 84 (26)
          Back pain 90 (28) 89 (28)
     Other disorder
          Cough 100 (31) 57 (18)
          Insomnia 73 (23) 82 (26)
Serious Adverse Events: The percentages of patients with grade 3 or 4 neutropenia in the elotuzumab group and the control group were 34% and 44%, respectively.  Grade 3 or 4 lymphocytopenia was seen in 77% of elotuzumab patients and 49% of control patients.
Percentage that Discontinued due to Adverse Events: Two patients discontinued treatment due to infusion reactions.
Study Author Conclusions Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death.

According to the Multiple Myeloma Research Foundation (MMRF), synergistic activity from the novel regimen of elotuzumab, lenalidomide, and dexamethasone shows promising results for the treatment of multiple myeloma.  They state that there are ongoing clinical trials and patients can still enroll in certain trials.  Additionally, the MMRF mentions an Expanded Access Program where patients who cannot participate in a clinical trial may receive investigational new drugs like elotuzumab.4

References

  1. Munshi NC, Longo DL, Anderson KC.Plasma Cell Disorders. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J.  Harrison’s Principles of Internal Medicine, 19eNew York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com/content.aspx?bookid=1130&Sectionid=79732153. Accessed August 25, 2015.
  2. Bristol-Myers Squibb and AbbVie Receive U.S. FDA Breakthrough Therapy Designation for Elotuzumab, an Investigational Humanized Monoclonal Antibody for Multiple Myeloma. Bristol-Myers Squibb. http://news.bms.com/press-release/rd-news/bristol-myers-squibb-and-abbvie-receive-us-fda-breakthrough-therapy-designatio. Accessed August 26, 2015.
  3. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015;373(7):621-31. doi: 10.1056/NEJMoa1505654.
  4. Multiple Myeloma Knowledge Center: Experimental Treatments. Multiple Myeloma Research Foundation. http://www.themmrf.org/multiple-myeloma-knowledge-center/experimental-treatments/elotuzumab/. Accessed August 26, 2015.
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