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Keywords:

  • myelomatous meningitis;
  • complication;
  • treatment;
  • outcome;
  • involved-field radiotherapy;
  • intracerebrospinal fluid chemotherapy

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

The most frequent nervous system complications of multiple myeloma are peripheral neuropathy and epidural spinal cord compression. Myelomatous meningitis (MM) has been considered rare. The current study was performed to characterize the clinical presentation, treatment, and outcome of MM.

METHODS

The study was a case series of 14 patients with cerebrospinal fluid (CSF)-positive MM who were treated at a tertiary care university medical center.

RESULTS

Fourteen patients with advanced multiple myeloma were treated with involved-field radiotherapy (to the brain in 5 patients and the spine in 6 patients) and intra-CSF chemotherapy (ventricular in 10 patients and lumbar in 4 patients). The best response to treatment included 6 partial responses and 8 patients with progressive disease. The median duration of response was 2.5 months (range, 0–6 months). Cause of death was progressive neurologic disease in 6 patients, combined systemic and neurologic disease in 6 patients, and systemic disease progression in 2 patients.

CONCLUSIONS

MM is rare and morbid entity (6-month neurologic disease progression-free survival rate of 7%), and appears to be no more responsive to treatment than solid tumor carcinomatous meningitis. Cancer 2008. © 2008 American Cancer Society.

Multiple myeloma, the most common plasma cell dyscrasia (with approximately 20,000 new cases diagnosed each year in the U.S.), is frequently accompanied by neurologic complications, most often peripheral neuropathies (both disease-related and treatment-related) and epidural spinal cord compression. Neoplastic meningitis secondary to multiple myeloma, so-called myelomatous meningitis (MM), is rare and to our knowledge has been infrequently reported.1–8

Neoplastic meningitis is a devastating complication of cancer. The overall frequency of neoplastic meningitis varies as a function of tumor type, but in general occurs in 1% to 5% of all patients with cancer.9–12 The treatment of neoplastic meningitis is almost never curative and therefore treatment goals are palliative, with attempted preservation of neurologic function.

To our knowledge, there is a paucity of randomized clinical trials in patients with neoplastic meningitis. As a consequence, there is no universally accepted treatment approach.9–12 Four chemotherapeutic agents (cytarabine liposome injection, methotrexate, cytosine arabinoside [ara-C], and thiotepa) are used in the treatment of neoplastic meningitis, with only modest differences noted among the agents with respect to toxicity or efficacy.9–12

This case series of 14 consecutive patients with MM had 2 principal objectives: to characterize the clinical presentation of MM and to determine response to MM-directed therapy administered in a standardized manner.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Study Overview

This was a prospectively collected case series from 3 centers (the University of Southern California, the H. Lee Moffitt Cancer Center, and the University of Massachusetts) in which patients with cytologically documented MM and no prior intracerebrospinal fluid (intra-CSF) therapy were treated between January 2000 and June 2007.

Patients

All patients included in this report had histologically proven multiple myeloma with a positive (recorded as positive not suspicious or atypical) CSF cytology within 14 days of the first intra-CSF therapy. The majority of patients had received some form of central nervous system (CNS)-directed radiotherapy before the diagnosis of MM, but none had received prior intra-CSF chemotherapy (Table 1). A radioisotope CSF flow study was performed in all patients. CSF compartmentalization (ie, CSF flow disturbance) not corrected by radiotherapy or the need for a ventriculoperitoneal shunt excluded patients from receiving intra-CSF chemotherapy. Concurrent systemic chemotherapy was administered, as appropriate, for the treatment of disease outside of the meninges. Patients with symptomatic or radiographically visible CNS disease were treated with local radiotherapy during the intra-CSF chemotherapy induction period but concurrent whole brain or craniospinal radiation was not permitted.9–12

Table 1. Myelomatous Meningitis
Patient no.Sex/age, yearsKPSCNS site of involvementCranial nerve involvementPrior CNS-directed therapyPretreatment CSF flow study
BrainSpine25 (Mentalis syndrome)3, 4, or 678RT for ESCCRT for skull metastases
PriorConcurrent
  • KPS indicates Karnofsky performance status; CNS, central nervous system; RT, radiotherapy; ESCC, epidural spinal cord compression; CSF, cerebrospinal fluid; +, positive; LS, lumbar spine.

  • *

    Cranial neuropathies.

  • Cauda equina syndrome.

  • Encephalopathy.

  • §

    Radiculopathy.

1Man/6480+*+ ++  +  Normal
2Man/8460+        +Normal
3Woman/6180+* +  + +  Normal
4Man/7660++        Spinal block, resolved with RT
5Man/5570 +§        Normal
6Woman/7070++     +  Normal
7Man/4690+*  ++     Convexity block, resolved with RT
8Man/4990+*++++++ + Normal
9Woman/5980 +§        Normal
10Man/6760 +§       +Normal
11Woman/5170+*+§ + + +  Convexity block, resolved with RT
12Man/6380+*  ++    +Convexity delay, no block
13Woman/6980 +     + +Irregularity in LS, no block
14Man/6270+*+  +     Normal

Intra-CSF Chemotherapy

Patients received 50 mg of liposomal ara-C (DepoCyt; Skyepharma, San Diego, Calif) by intraventricular or intralumbar injection every 14 days for a total of 4 weeks (3 total doses). This initial 4-week interval constituted induction. The use of extended-release liposomal ara-C was selected based on the results of 2 randomized trials and the fact that all patients had failed multiple prior therapies including alkylator-based chemotherapy.11, 12 Liposomal ara-C was obtained commercially, billed to third-party payers, and the study was conducted without corporate support. Patients who were clinically stable or improved and who had converted from positive to negative CSF cytology at all previously positive sites continued on to maintenance therapy. During maintenance, patients received 50 mg of liposomal ara-C once every 4 weeks (7 total doses). In patients who were clinically stable or improved and who maintained negative CSF cytology, maintenance therapy continued until disease progression. A cycle of liposomal ara-C was defined as 4 weeks of therapy, during which patients received either 3 doses of liposomal ara-C (during induction) or 1 dose of liposomal ara-C (during maintenance). Dexamethasone (at a dose of 4 mg given orally twice per day for 5 days) was prescribed for mitigation of liposomal ara-C-induced arachnoiditis as is customary with this agent, and may have contributed to response to intra-CSF liposomal ara-C. No intra-CSF steroids were used.

Clinical and Laboratory Monitoring

After the diagnosis of MM by positive CSF cytology, all patients were evaluated with contrast-enhanced brain and complete spinal magnetic resonance imaging and radio-isotope CSF flow studies.11, 12

Before each treatment with liposomal ara-C, patients underwent a complete neurologic history and examination, measurement of hematologic and serum chemistry parameters, and a ventricular (in patients with Ommaya reservoirs) or lumbar CSF cytology. In responding patients, a confirmatory lumbar CSF cytology was assessed. CSF cytology results were reported by the cytopathologist as unsatisfactory, negative, abnormal, suspicious, or malignant. For purposes of analysis, cytology examinations interpreted as suspicious were scored as positive and those interpreted as abnormal were scored as negative.9–12

Patients were considered responders if their CSF cytology converted from positive to negative at all sites previously shown to be positive and they remained neurologically stable or improved at the conclusion of induction.9–12 Patients were considered nonresponders if they had positive or suspicious CSF cytology at the end of the induction period (4 weeks after the initiation of treatment) or if they demonstrated neurologic disease progression regardless of CSF cytology. A complete response was defined as the conversion of positive CSF cytology to negative and the resolution of all pretreatment neurologic deficits.9–12 A partial response was defined as conversion from positive to negative CSF cytology and either stable or improved pretreatment neurologic deficits. All other outcomes were considered progressive disease. Patients were considered evaluable for response if they received at least 1 dose of intra-CSF liposomal ara-C and had at least 1 on-treatment CSF examination. Neither CSF immunocytopathology nor cytogenetics was performed. Cause of death was determined by 1 of the authors and was based on the physical and neurologic examinations, radiographic and laboratory studies assessing the extent of extraneural disease, and all other clinical data available before death.

Identification of episodes of drug-related arachnoiditis was based on an operational definition of whether patients developed, within 3 days of drug injection, neck rigidity, neck pain, meningismus, nausea, vomiting, headache, fever, confusion, or aseptic CSF pleocytosis.11, 12 Arachnoiditis was graded on the basis of the highest grade of any of the constellation of adverse events characterized as mild (grade 1), moderate (grade 2), severe (grade 3), or life-threatening (grade 4). All other toxicities were defined according to the National Cancer Institute Common Toxicity Criteria (version 3).

Analysis

In patients who discontinued intra-CSF liposomal ara-C because of toxicity, response was the best-recorded response through the cessation of intra-CSF liposomal ara-C. For all patients, overall survival was measured from the date of the initiation of liposomal ara-C therapy to death. Time to neurologic disease progression was measured from the date of the initiation of intra-CSF liposomal ara-C therapy to the date of neurologic disease progression. Kaplan-Meier plots depicting progression-free and overall survival were produced and 95% confidence intervals were calculated.13 The Fisher exact test was used to compare cause of death in patients responding to treatment and those not responding to treatment.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Characteristics

Fourteen consecutive patients (9 men and 5 women) comprised this case series (Table 1). The ages of the patients ranged from 46 to 84 years (median, 62.5 years). All patients had recurrent extraneural multiple myeloma and had failed multiple prior therapies (median of 3 therapies), including bone marrow transplantation (11 of 14 patients) (Table 2). Systemic disease at time of the diagnosis of MM was manifested by bone marrow involvement (14 of 14 patients), renal insufficiency (6 of 14 patients), hypercalcemia (3 of 14 patients), and plasma cell leukemia (2 of 14 patients). Neurologic presentation (Table 1) included cranial neuropathy in 7 patients (involvement of cranial nerve II in 2 patients; cranial nerve V in 5 patients; cranial nerves III, IV, and VI in 5 patients; cranial nerve VII in 2 patients; and cranial nerve VIII in 1 patient), cauda equina syndrome in 6 patients, radiculopathy in 4 patients (1 with concomitant epidural spinal cord compression), and encephalopathy in 3 patients. The duration of neurologic symptoms and signs before the recognition of MM ranged from 2 to 12 weeks (median of 4 weeks). Eight patients had received prior CNS-directed radiotherapy (5 for epidural spinal cord compression and 4 for metastases at the base of the skull). All patients underwent radio-isotope CSF flow studies and 3 required involved-field radiotherapy to sites of CSF flow block (cerebral convexities in 2 patients and the spine in 1 patient). In addition, 7 patients had bulky neuroradiographic disease identified by neuraxis magnetic resonance imaging, all of whom received limited-field radiotherapy (5 to the spine and 3 to the brain). One patient received cranial irradiation because of MM-related encephalopathy. At the conclusion of limited-field radiotherapy, all 8 patients who underwent radiotherapy had positive CSF cytologies. Six patients received concurrent tumor-specific systemic chemotherapy. All patients had received extensive prior therapy (median of 4 prior chemotherapies; 11 patients had undergone transplantation) (Table 1). Ten patients received drug via the intraventricular route through an Ommaya reservoir, whereas 4 patients received intra-CSF drug by the lumbar route. Patients received a total of 55 cycles of liposomal ara-C with a median of 3.5 cycles administered per patient (range, 1–7 cycles).

Table 2. Myelomatous Meningitis
Patient no.Prior or concurrent systemic chemotherapyCNS-directed therapy
RadiotherapyIntra-CSFchemotherapy/ no. of cyclesResponse/ duration, monthsSurvival in months/ cause of death
VADThalidomide ± dexamethasoneBortezomibAlkylatorBMTBrainSpine
  1. VAD indicates vincristine, doxorubicin (adriamycin), and dexamethasone; BMT, bone marrow transplantation; CNS, central nervous system; CSF, cerebrospinal fluid; +, positive; V, intraventricular; PD, progressive disease; MM, myelomatous meningitis; L, intralumbar; PR, partial response; C, combined myelomatous meningitis and systemic disease; S, systemic disease.

1+++++ ++/3VPD/23/MM
2++++   +/3LPD/23/MM
3++++++ +/5VPR/34/C
4++++  ++/3LPD/23/S
5+++++  +/6VPR/45/MM
6++++  ++/2LPD/24/C
7++++++ +/4VPR/35/C
8++++++++/7VPR/68/S
9+++++  +/6VPR/45/C
10+++++  +/2LPD/24/MM
11++++++ +/4VPD/34/MM
12++  ++ +/6VPR/35/C
13++  + ++/3VPD/03/C
14+++++ ++/1VPD/02/MM

Response

All patients were evaluable for response; however, only 11 of 14 patients (78%) completed induction therapy with liposomal ara-C (Table 2). Three of the 14 patients (22%) progressed clinically during induction therapy. Six of the 14 patients (43%) treated with liposomal ara-C attained both partial neurologic and complete cytologic responses at the conclusion of the induction period, and continued on to maintenance therapy. Five patients (35%) were stable neurologically, but had persistently positive CSF cytologies at the conclusion of induction therapy. They were offered alternative therapy or supportive care. Time to neurologic disease progression ranged from <1 month to 6 months, with a median of 2.5 months. The median survival after the diagnosis of MM was 4.0 months (95% confidence interval, 3.3–4.7 months), with a range of 2 months to 8 months (Fig. 1). Three-month, 6-month, and 12-month survival probabilities were 50%, 7%, and 0%, respectively. Six patients died of progressive neurologic disease, 6 died of combined neurologic and systemic disease progression, and 2 died of progressive systemic disease.

thumbnail image

Figure 1. Progression-free survival (PFS) and overall survival (OS) of neurologic disease in patients with myelomatous meningitis.

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Toxicity

Toxicity manifested primarily as a transient arachnoiditis, appearing within 1 to 3 days of treatment with liposomal ara-C. Arachnoiditis of any grade occurred in 7 patients (50%) and in 33% of all treatment cycles (18 of 55 cycles). However, only 2 patients (14%) had >grade 2 arachnoiditis (4 of 55 [7%] of all treatment cycles). Arachnoiditis was easily managed with oral steroids, analgesics, antiemetics, and antipyretics. Arachnoiditis resolved within 2 to 3 days after the administration of liposomal ara-C in all patients. No patient required hospitalization or a delay in treatment, nor was a treatment-related death recorded. No evidence of hematologic toxicity related to liposomal ara-C was noted. Chronic fatigue, presumed to be related to intra-CSF therapy, was noted in 4 patients (28%); however, fatigue may also have been related to systemic therapies or to the disease itself. In no patient was fatigue classified as >grade 3. Psychostimulant medication (methylphenidate or modafinil) was used successfully for treatment-related chronic fatigue in 5 patients.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In a prior report that to our knowledge constituted the largest series of patients (n = 23) with MM reported to date, the incidence of MM was estimated at 1.1%, indicating the infrequent occurrence of leptomeningeal metastases in multiple myeloma.1 In the current series, the estimated incidence of MM was 0.8% based on the total number of patients seen with multiple myeloma per year at a single institution and the number of patients identified with MM. Why MM is so uncommon is to our knowledge unclear, particularly when contrasted with other hematologic malignancies such as acute lymphocytic leukemia and non-Hodgkin lymphoma, in which neoplastic meningitis is frequent. Multiple myeloma does commonly produce skull base and epidural involvement, complicating and potentially delaying the diagnosis of MM. As documented in this series, however, patients with MM typically present with a spectrum of neurologic signs and symptoms that are clearing distinguishable from those related to the other CNS manifestations of multiple myeloma. Cranial nerve deficits in MM usually involve the upper cranial nerves (nerves II–VII); base of skull involvement, in contrast, usually produces lower cranial nerve (nerves IX–XII) deficits. Encephalopathy, which was observed in 3 of the 14 patients in the current study, would not be expected in patients with base of skull involvement. Finally, radiculopathy and cauda equina syndrome are common in MM, whereas pain and signs and symptoms of myelopathy usually accompany epidural spinal cord compression from multiple myeloma.

The treatment of neoplastic meningitis remains challenging for several reasons. First, to our knowledge there is no widely accepted therapeutic approach, although multimodal treatment, including radiotherapy and both systemic and intra-CSF chemotherapy, is commonly used. Second, patients with neoplastic meningitis often present late in their disease course and consequently often have a large systemic tumor burden that is often refractory to treatment. Finally, a limited repertoire of chemotherapeutic agents suitable for intra-CSF administration exists.9–12 Three agents are frequently used (cytosine arabinoside, methotrexate, and thiotepa), based on a limited number of phase 3 trials.9–12 Recently, a slow-release liposomal formulation of cytosine arabinoside, DepoCyt, has been marketed and is indicated for the treatment of neoplastic meningitis.11, 12 Nonetheless, new agents for the treatment of neoplastic meningitis are much needed.

The current case series did demonstrate evidence of antimyeloma activity, with a 43% response to treatment after 4 weeks (3 cycles) of induction treatment. This level of activity is comparable to that noted in prior studies. The response to intra-CSF liposomal ara-C reported in the current study reflects both the use of involved-field radiotherapy to sites of symptomatic disease, radiographically identified bulky disease or identified regions of CSF flow interruption, concomitant oral dexamethasone (given 5 days with each liposomal ara-C administration), and the use of myeloma-specific systemic chemotherapy in appropriate patients. However, the majority of prior studies of patients with neoplastic meningitis have used a similar multimodal approach to the treatment of leptomeningeal metastases and this study does not differ in that regard. Unfortunately, the responses in the current study proved not to be durable when compared with other trials (7% vs 15% 6-month freedom from neurologic disease progression). This observation suggests that trials focusing on specific tumor histology are useful to clarify response and the duration of response in organ-specific cancers. In addition, MM was the sole (6 patients) or an important contributing (6 patients) cause of death, suggesting that better therapies directed at this disease complication are urgently required. It is interesting to note that 1 recent study suggested that neoplastic meningitis in patients with breast cancer may be managed equally well by focal radiotherapy and concurrent tumor-appropriate systemic chemotherapy without the addition of intra-CSF chemotherapy.14 The role of intra-CSF chemotherapy in patients with neoplastic meningitis in general warrants further study.

In conclusion, MM typically presents with a spectrum of neurologic signs and symptoms that facilitates its recognition and usually allows clinicians to distinguish MM from the more common CNS complications of skull base and epidural manifestations of multiple myeloma. Unfortunately, the results of the current study suggest that MM-directed therapy (intra-CSF liposomal ara-C, involved-field radiotherapy, and systemic chemotherapy) has only modest activity(6-month neurologic disease-free progression rate of 7%; median survival of 4 months). New approaches, perhaps utilizing intra-CSF monoclonal antibodies or targeted therapies, should be undertaken.15

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES