ABSTRACT

Osteolytic lesions are present in 75% of multiple myeloma (MM) patients and frequently require palliation with radiation therapy (RT). Case series of MM patients with bone pain undergoing palliative RT suggest doses ≥ 12 Gy (EQD2) provide excellent bone pain relief. However, recent advances in novel biologic agents have significantly improved overall survival and quality of life for MM patients. We hypothesized that lower-dose RT (LDRT, EQD2 < 12 Gy) offers an effective alternative to higher-dose RT (HDRT, EQD2 ≥ 12 Gy) for palliation of painful, uncomplicated MM bone lesions. We retrospectively identified MM patients treated with RT for uncomplicated, painful bone lesions and stratified by EQD2 ≥/< 12 Gy. Clinical pain response (CPR) rates, acute and late toxicity, pain response duration, and retreatment rates between LDRT and HDRT groups were analyzed. Thirty-five patients with 70 treated lesions were included: 24 patients (48 lesions) treated with HDRT and 11 patients (22 lesions) with LDRT. Median follow up was 14 and 16.89 months for HDRT and LDRT, respectively. The median dose of HDRT treatment was 20 Gy versus 4 Gy in the LDRT group. The CPR rate was 98% for HDRT and 95% for LDRT. There was no significant difference in any-grade acute toxicity between the HDRT and LDRT cohorts (24.5% vs. 9.1%, Χ2 p=0.20). Pain recurred in 10% of lesions (12% HDRT versus 9.5% LDRT). Median duration of pain response did not significantly differ between cohorts (p=0.91). Five lesions were retreated, 2 (9.5%) in the LDRT cohort and 3 (6.3%) in the HDRT cohort. In this study, LDRT effectively palliated painful, uncomplicated MM bony lesions with acceptable CPR and duration of palliation. These data support prospective comparisons of LDRT versus HDRT for palliation of painful, uncomplicated MM bony lesions.

INTRODUCTIONMultiple myeloma is the most common plasma cell neoplasm, with approximately 30,000 new diagnoses annually in the United States1Rajkumar SV Dimopoulos MA Palumbo A et al.International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.. Osteolytic lesions are present in 75% of MM patients at diagnosis and bone pain is the most common presenting symptom2Tsang RW Campbell BA Goda JS et al.Radiation Therapy for Solitary Plasmacytoma and Multiple Myeloma: Guidelines From the International Lymphoma Radiation Oncology Group.,3Rudzianskiene M Inciura A Gerbutavicius R et al.Single vs. multiple fraction regimens for palliative radiotherapy treatment of multiple myeloma: A prospective randomised study.. MM is incurable and patients historically had limited therapeutic options. Over the past 20 years, however, the advent of novel systemic agents has significantly improved the overall survival and quality of life for MM patients4Kumar SK Dispenzieri A Lacy MQ et al.Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients..Radiotherapy (RT) is a valuable adjunct for the palliation of painful MM bone lesions and is extremely effective, with clinical pain responses (CPR) in up to 97% of patients5Leigh BR Kurtts TA Mack CF Matzner MB Shimm DS. Radiation therapy for the palliation of multiple myeloma.. Several studies examining the relationship between CPR and RT dose suggest that doses (EQD2) of 12Gy or more (i.e., 8Gy/1Fx, 20Gy/5Fx, 30Gy/10Fx) all provide similar palliation for uncomplicated bone lesions3Rudzianskiene M Inciura A Gerbutavicius R et al.Single vs. multiple fraction regimens for palliative radiotherapy treatment of multiple myeloma: A prospective randomised study.,5Leigh BR Kurtts TA Mack CF Matzner MB Shimm DS. Radiation therapy for the palliation of multiple myeloma.,6Local radiotherapy for palliation in multiple myeloma patients with symptomatic bone lesions.. Much of these data, however, are based on case series or retrospective analyses analyzing patients before the modern era of novel systemic agents for MM. Compared to higher dose palliative RT (HDRT, EQD2 ≥ 12 Gy), low-dose palliative RT (LDRT, EQD2 METHODS AND MATERIALSWe retrospectively identified all consecutively treated MM patients treated with RT for painful, uncomplicated bone lesions at XXXX and YYYY by query of electronic radiation treatment records from 2013-2019. Uncomplicated osseous lesions were defined as all lesions without impending risk of pathologic fracture, prior orthopedic fixation, or spinal lesions with malignant epidural involvement. Epidural disease was excluded as longer course of RT may benefit this subset of patients. 7Rades D Hoskin PJ Stalpers LJA et al.Short-course radiotherapy is not optimal for spinal cord compression due to myeloma.. Likewise, patients with pathologic fractures were excluded as RT would not be expected to alleviate pain. Impending pathologic fractures were identified utilizing Mirels’ criteria. All patients underwent CT simulation and were treated with standard palliative RT fields. GTV volume encompassed only areas of osseous lesions within involved bones and was delineated using Eclipse (Varian, Palo Alto, CA). A treatment site was defined as a bony lesion(s) able to be treated by a single set of radiation fields. Reirradiation was defined as a subsequent palliative RT overlapping the prescription dose of a previous RT course.

Clinical practice at XXXX incorporated both LDRT and HDRT based on physician/patient preference; only HDRT was utilized at YYYY. Patients were grouped into the LDRT cohort with EQD2 < 12 Gy, with all others treated with EQD2 ≥ 12Gy comprising the HDRT cohort. For EQD2 calculations an α/β ratio of 10 was used. Patients were routinely seen in follow-up after the completion of RT and assessed for pain response and toxicity beginning at 1-3 months post-RT, and typically again at 6 months per clinic standards utilizing both physician and patient reported pain response metrics, following which patients were either followed in radiation oncology or discharged for long term medical oncology follow-up.

Pain responses were reported as complete (absence of presenting pain without opiates), partial (improved pain with stable/decreased opiates), or none (worsened pain and/or increased opiates). Complete and partial responses were considered CPRs. No patients began new systemic therapies or steroids during RT. Clinical data were collected compositely by chart review of radiation and medical oncology clinic notes and inpatient admission notes. The primary endpoint was CPR at each specific treated site. Secondary endpoints were acute and late toxicity, duration of pain response, retreatment rates, and overall survival from date of RT initiation. This retrospective protocol was approved by both the XXXX and YYYY IRBs.

Toxicities were recorded retrospectively using the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0) and reported by type and grade. If patients required retreatment, the additional course of RT was noted and included in the analysis. Patients were recorded as having received systemic therapy prior- or post-RT if administered within 3 months of RT initiation.

Patient demographic and disease characteristics were summarized using descriptive statistics. Baseline differences in patient characteristics were assessed using the chi-squared test. Actuarial rates of CPR, acute toxicity, and retreatment were calculated based on assessment at acute toxicity visits and up to 90 days post-RT. Differences in CPR between RT regimens were compared using the chi-square test. Median time to event for pain recurrence was determined by the Kaplan-Meier method. All statistical tests were two-sided with α=0.05 considered significant. Statistical analyses were performed utilizing R software.

RESULTSThirty five patients with 70 treated lesions were included; 11 patients received LDRT to 22 lesions and 24 patients received HDRT to 48 lesions (Table 1). The LDRT cohort includes one patient that subsequently received HDRT reirradiation. Median follow-up was 16.8 months (interquartile range [IQR]=2.3-29.1 months) versus 14.0 months (IQR=5.9-31.2), respectively. Median age at first palliative RT was 66 (range, 57-86) for LDRT and 63.5 (range, 42-88) for HDRT. The median time from diagnosis to start of RT was longer in the HDRT cohort (65.7 versus 5.1 months, pTable 2). The median dose of HDRT was 20Gy (range=8-30Gy, EQD2=12-32.5Gy) versus 4Gy for LDRT (range=4-8Gy, EQD2=4.67-9.3Gy, Supplemental Table 2). The median GTV volume was significantly greater in the LDRT cohort (median = 104.5, IQR = 34.9-197.3) versus the HDRT cohort (median = 20.7, IQR = 9.0-43.9, p

Table 1Patient demographic and disease characteristics. (n=35 patients)

1Wilcoxon Rank Sum Test; 2Fisher Exact Test, 3Mann-Whitney Test

Table 2Treatment related characteristics. (n=70 sites)

The overall effectiveness of HDRT versus LDRT was evaluated based on CPR at 6 months post-RT and pain response duration. The overall CPR rate was 97%, with 98% of HDRT and 95% of LDRT responding either partially or completely (Figure 1, p=0.53). Median time to pain response was 37.5 and 39 days, respectively. There was no significant difference in the duration of pain response between HDRT and LDRT cohorts (p = 0.91, Figure 2). The median pain response duration was not yet reached for either cohort. Additionally, there was no difference in OS between the patient cohorts (p=0.74, Supplemental Figure 2).

Figure 1Percentage of clinical pain responses (CPR) in patients receiving HDRT and LDRT. There was no significant difference between the number of patients experiencing a pain response (complete/partial) versus those with no pain response to radiation therapy (Fisher's exact p=0.53).

Figure 2Freedom from pain recurrence was calculated by the Kaplan-Meier method for the HDRT and LDRT cohorts. There was no statistically significant difference in the duration of pain responses to radiation therapy (log rank p =0.91).

There was no significant difference in all grades of acute or late toxicity between the HDRT (24.5%) and LDRT cohorts (9.5%, p=0.20, Figure 3, Supplemental Table 3). In the overall cohort, pain recurred in 10% of lesions (12.5% HDRT versus 9.1% LDRT). Five lesions were retreated, 2 (9.1%) in the LDRT cohort and 3 (6.3%) in the HDRT cohort (Table 3). Of the retreated LDRT patients, one had pathologic fracture and the other had subsequent CPR with HDRT reirradiation.

Figure 3Acute toxicity events following HDRT and LDRT. There was no statistically significant difference in episodes of acute toxicity following RT (Fisher's exact p=0.20).

Table 3Treatment related outcomes. (n=70 sites)

DISCUSSION

In this study LDRT, often delivered in a single 4 Gy fraction, was effective for palliation of painful, uncomplicated MM lesions. The rates of CPR and pain response duration were similar between LDRT and HDRT despite larger overall GTV volumes for the LDRT patients. Moreover, pain recurrence rates were not increased in LDRT patients. A lower percentage of LDRT patients experienced acute toxicity. Our data suggest that LDRT has the potential to effectively palliate painful MM bony lesions with acceptable CPR and duration of palliation.

While, some previous reports8Matuschek C Ochtrop TA Bölke E et al.Effects of Radiotherapy in the treatment of multiple myeloma: a retrospective analysis of a Single Institution.,9Wang S Salgado LR Adler A et al.Dose Selection for Multiple Myeloma in Modern Era. suggested higher doses of palliative RT may provide superior CPR or more durable pain responses for uncomplicated bony lesions, others3Rudzianskiene M Inciura A Gerbutavicius R et al.Single vs. multiple fraction regimens for palliative radiotherapy treatment of multiple myeloma: A prospective randomised study.,5Leigh BR Kurtts TA Mack CF Matzner MB Shimm DS. Radiation therapy for the palliation of multiple myeloma.,6Local radiotherapy for palliation in multiple myeloma patients with symptomatic bone lesions. have not. Additionally, none have examined the use of LDRT. Our findings are consistent with a recent retrospective osseous plasmacytoma series, in which RT doses as low as 20Gy, ∼50% lower than typical ILROG recommendations of 35-50Gy, provided effective local control2Tsang RW Campbell BA Goda JS et al.Radiation Therapy for Solitary Plasmacytoma and Multiple Myeloma: Guidelines From the International Lymphoma Radiation Oncology Group.,10

Elhammali A, Amini B, Ludmir EB, et al. New Paradigm for Radiation in Multiple Myeloma: lower yet effective dose to avoid radiation toxicity. Haematologica. January 2020. doi:10.3324/haematol.2019.235804

. Together, these data suggest a need to assess RT de-intensification in MM and plasmacytoma.LDRT possesses many hypothetical advantages to HDRT. These include less toxicity, shorter treatment course, and lower cost11Role of radiation therapy in palliative care of the patient with cancer.. The LDRT dose we commonly employed was sufficiently low that salvage reirradiation with LDRT or HDRT would be feasible based on the initial CPR12Chow E van der Linden YM Roos D et al.Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial.. LDRT may be a good option for newly diagnosed MM patients as they will likely respond to planned systemic therapy. This is consistent with the noted imbalance in our patient cohort that LDRT patients were more likely to have recently diagnosed disease, that is not relapsed of refractory to prior lines of therapy. Additionally, lower RT doses may theoretically preserve marrow for subsequent stem cell transplantation13Casamassima F Ruggiero C Caramella D Tinacci E Villari N Ruggiero M. Hematopoietic bone marrow recovery after radiation therapy: MRI evaluation., which becomes a more pertinent concern in an era of increased patient survival with MM. Future analyses may assess long term peripheral blood counts to examine this hypothesis as this requires long-term follow-up not feasible in the retrospective setting.Additionally, medical oncologists may more comfortably continue systemic therapy during LDRT for low-risk disease sites, thereby avoiding treatment breaks, given reports of the safety of concurrent therapy14Resende Salgado L Wang S Adler A et al.The Safety Profile of Concurrent Therapy for Multiple Myeloma in the Modern Era.,15Shin SM Chouake RJ Sanfilippo NJ et al.Feasibility and efficacy of local radiotherapy with concurrent novel agents in patients with multiple myeloma.. Indeed, 18% of patients receiving LDRT received concurrent systemic therapy. Even if the pain response duration were shorter with LDRT than HDRT, LDRT could potentially spare a subset of patients from a higher total RT dose. Given the prior delivered dose, retreatment would likely be straightforward. While it is possible that retreatment rates may be higher with LDRT, this was not observed in our, albeit small, LDRT patient cohort.There are multiple limitations to our study. Clinical endpoints were assessed retrospectively from a relatively small cohort. Patients were also seen by multidisciplinary teams including radiation and medical oncology, and palliative care, allowing for potential variations in pharmacologic pain management which may have influenced CPR. Clinical correlation of CPR with subsequent imaging studies to visualize a corresponding radiographic response or recurrence was also unavailable. Notably, all patients receiving LDRT were treated at the YYYY,were more commonly African-American and male, and therefore may not be representative of the general population16Agha Z Lofgren RP VanRuiswyk JV Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use.. Based on the limited sample size, statistical modeling of these imbalances were not possible. While dose selection was physician driven, we cannot exclude the possibility that other patient or disease attributes were considered. Similarly, HDRT patients had longer times to RT from diagnosis, suggesting greater percentages had relapsed or refractory disease. In addition to evaluating the efficacy of LDRT prospectively, future studies should identify patient factors to determine which patients would benefit from LDRT versus HDRT.CONCLUSIONS

LDRT resulted in effective palliation of uncomplicated MM bony lesions in our patient cohort with favorabletoxicity and retreatment rates. These data support other studies utilizing reduced-dose RT for hematologic malignancies and support further inquiry into the use of palliative LDRT for low-risk MM patients with uncomplicated MM bony lesions.

Data Sharing: De-identified, individual patient data available through controlled data repository with VA approval upon request.

SUMMARY

We hypothesized that lower-dose RT (LDRT, EQD2<12Gy) offers an alternative to higher-dose RT (HDRT, EQD2≥12Gy) for palliating painful, uncomplicated MM bone lesions. Twenty-four patients (48 lesions) treated with HDRT and 11 patients (22 lesions) treated with LDRT were assessed. CPR rate was 98% for HDRT and 95% for LDRT, with similar rates of toxicity and pain recurrences. LDRT effectively palliated painful, uncomplicated MM bony lesions with acceptable CPR and should be analyzed prospectively.

Data Sharing

De-identified, individual patient data available through controlled data repository with VA approval upon request.

Disclosures

None

Funding

None

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Single vs. multiple fraction regimens for palliative radiotherapy treatment of multiple myeloma: A prospective randomised study.

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Radiation therapy for the palliation of multiple myeloma.

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Short-course radiotherapy is not optimal for spinal cord compression due to myeloma.

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Effects of Radiotherapy in the treatment of multiple myeloma: a retrospective analysis of a Single Institution.

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Arch Intern Med. 160: 3252-3257Article InfoPublication History

Accepted: May 14, 2021

Received in revised form: February 8, 2021

Received: July 9, 2020

Publication stageIn Press Journal Pre-ProofIdentification

DOI: https://doi.org/10.1016/j.adro.2021.100729

Copyright

© 2021 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

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