Discontinuation due to the high response rate at the 1st stage and slow accrual.

This study was done to find out if the investigational medication, rituximab, could help relieve the symptoms of peripheral neuropathy (such as numbness [abnormal protein in the blood] and weakness of the lower and upper extremities) in people who have monoclonal gammopathy of undetermined significance and people with a symptomatic or smoldering Waldestrom macroglobulinemia.

Rituximab is an antibody which attacks a particular type of white blood cell (B Cell). By targeting the B-cells which make the abnormal protein which is involved in causing the nerve trouble, it is hoped that damage to nerve fibers will be stopped and improvement will be allowed to proceed.

This was a Phase II single arm trial evaluating the use of Rituximab administered at standard dose and schedule as an initial cycle of therapy, followed by a re-evaluation at 6 months.

If progression in neuropathy (as indicated by an increase in the Neuropathy Impairment Score (NIS) of greater than or equal to 10 or a modified Rankin Score increase of > 1 grade) the patient was off study. In addition, if the subject elected to pursue other active treatment including but not limited to plasmapheresis, high-dose intravenous immuneglobulin (IVIG), chemotherapeutic agents, or high dose corticosteroids, or if conditions in the exclusion criteria develop subsequent to enrollment, the subject was off study.

If the neuropathy is stable or responding (NIS of < 10 or a modified Rankin Score increase of < 1 grade) the patient would have received Cycle 2 of rituximab followed by a reevaluation at 12 months.

The study had a Simon Optimal two-stage Phase II design (α 5%, β 10%, π0 5%, π1 20%). The minimum clinically important response rate was 20%. The first stage was to include 21 patients and the second stage a total of 41 patients. The treatment would be rejected if there were fewer than 2 responders at the first stage or fewer than 5 responders at the second stage. The treatment would be accepted for further study if there were at least 5 responders out of 41 patients.

DISEASE CHARACTERISTICS:

• Diagnosis of monoclonal gammopathy of undetermined significance (MGUS), as evidenced by 1 of the following criteria:

  • Documented monoclonal protein in the serum (< 3 g/dL) or urine
  • Monoclonal serum free light chain, with at least 50% of patients having an immunoglobulin M (IgM) paraprotein (the balance being immunoglobulin G (IgG) or immunoglobulin A (IgA) subtypes)

• Neuropathy Impairment Score (NIS) ≥ 25

• Stable or progressive neuropathy (i.e., not currently improving), as judged by NIS values that have not fallen ≥ 10 (between enrollment and the last documented value), at least 1 month but not greater than 3 months prior to enrollment

• No evidence of amyloidosis or overt lymphoma, overt myeloma, or Waldenström macroglobulinemia with end organ damage

• No evidence of multiple myeloma, Amyloid Light-chain (AL)-amyloidosis

• No evidence of Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, diabetes mellitus, alcohol induced neuropathy, untreated hypothyroidism, vitamin B12 deficiency, Sjögren syndrome, and other causes of neuropathy

PATIENT CHARACTERISTICS:

Inclusion Criteria:

• Not pregnant

• Negative serum pregnancy test

• Fertile patients must use an acceptable method of birth control during treatment and for 6 months after completion of treatment

  • One of the following birth control measures must be used: birth control pills, intrauterine device, contraceptive injections (Depo-Provera), barrier methods such diaphragm, condom or contraceptive sponge with spermicide

• Adequate bone marrow function as indicated by sufficient precursors of all three cell lines and cellularity of at least 20% on bone marrow biopsy within 6 months

• Platelets > 100,000/mm^3

• Absolute neutrophil count (ANC) > 1,000/mm^3

• Hemoglobin > 7 g/dL

• Serum creatinine < 3.0 mg/dL

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2 times upper limit of normal

• No history of psychiatric disorder requiring hospitalization, psychiatric consultation, or psychotropic medications within the last year

  • Patients with controlled depression are eligible, as defined by the following:

    • Stable for at least 6 months
    • No increase in psychotropic medications

Exclusion criteria:

• History of HIV infection or seropositivity

• History or serological profile suggesting prior hepatitis B virus (HBV) infection (i.e., HbsAg or anti-HBs with anti-HBc)

  • Prior HBV vaccination with isolated anti-HBs antibodies is not an exclusion criterion

• HBV infection or non-vaccination-related HBV seropositivity

• Active infection

• New York Heart Association class III or IV heart disease

• History or baseline ECG tracing demonstrating severe recurrent or severe recent (within 3 months) cardiac dysrhythmia (e.g., ventricular tachycardia, torsades de pointes ("Twisting of the Points," a rapid polymorphic Ventricular Tachycardia), or other serious ventricular dysrhythmias) requiring implanted defibrillator treatment

• Confirmed diagnosis of systemic lupus erythematosus (SLE)

  • An isolated low titer positive antinuclear antibody test without clinical evidence of SLE is not an exclusion criterion

• Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix

• Malignancy associated with a paraneoplastic neuropathy

• A history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

• A history of known severe primary or secondary immunodeficiency (e.g., common variable immunodeficiency)

• Significant other uncontrolled medical illnesses that may interfere with drug delivery or interpretation of results

PRIOR CONCURRENT THERAPY:

• No live vaccine therapy within 30 days of enrollment
• No plasmapheresis within 3 months
• No high-dose intravenous immunoglobulin, chemotherapeutic agents, or high-dose corticosteroids (> 10 mg daily or every other day) within 3 months
• No systemic corticosteroids within 3 months (unless needed for adrenal insufficiency or at a stable dose ≤ 10 mg daily)
• No high-dose (> 250 mg/day) vitamin B6 within the past month
• No prior treatment with thalidomide or neurotoxic drugs (e.g., vinca alkaloids, taxol, or platinum)

Subjects were monitored for adverse events weekly per cycle ( Day 1, 8, 15, and 22); each subject could receive up to 2 cycles (4 infusions each.) Adverse event monitoring continued for at least 12 months following the subject's last Rituximab infusion.

The study was discontinued at the first stage to the high response rate and slow accrual.