Effectiveness and Safety of Integrative Therapies in Multiple Myeloma
Phase: NA
Conditions: Multiple Myeloma
Sponsor: Bnai Zion Medical Center

 
Cover page: 
 
Official Title of the study: 
 
Effectiveness and safety integrative therapies in multiple myeloma 
 
 
Date: July 15th, 2024 
 
 

Research Plan: 
 
Background: 
Multiple myeloma (MM) is a hematologic malignancy that can cause anemia, renal failure, 
bone disease, and hypercalcemia [1]. Today MM is considered a chronic disease and most 
patients will receive ongoing biological treatments. As a result, this disease causes a number 
of symptoms related to the disease itself or its treatment, which include, among others, 
weakness and fatigue, bone or nerve pain, depression and anxiety, gastrointestinal symptoms, 
impairment of sexual function, etc. These symptoms cause significant damage to quality-of-
life (QoL) [2] which is similar in patients who receive different treatment lines [3]. As a result, 
the FDA emphasized QoL as a key outcome for the approval of new drugs for the disease [4]. 
The conventional therapeutic approach to the various symptoms is based on supportive care 
guidelines including pharmacological and non-pharmacological treatment of pain, 
gastrointestinal symptoms, psychological components, etc [5]. These treatments involve side 
effects and usually refer to individual symptoms. 
Complementary and integrative medicine includes treatments of touch, movement, mind-body, 
acupuncture, nutrition and nutritional supplements. Many studies have shown the effectiveness 
of these treatments on various symptoms in cancer patients including pain, depression and 
anxiety, fatigue and weakness, gastrointestinal symptoms, etc [6-8]. In MM patients, the effect 
of diet and nutritional supplements was mainly examined, but there is also little information on 
the effectiveness of mind-body treatments on symptoms of anxiety and depression, as well as 
acupuncture on neuropathy or on symptoms experienced by MM patients around autologous 
bone marrow transplantation [9]. 
In recent years, a wide variety of new drugs have entered the market that cause side effects that 
were unknown until now and little is known about the effect of complementary medicine 
treatments on symptoms and QoL of MM patients since the development of these drugs. 
In this study we will examine the effect of complementary and integrative medicine treatments 
(including acupuncture, touch, movement, mind-body) on the QoL and symptoms that 
characterize MM patients during treatment with different lines of therapy, including new drugs. 
Study aims: 

In the present study, we aimed to evaluate if integrative therapies may improve QoL, 
symptoms, financial and social aspects as well as the disease course of MM patients. 
Study plan: 
Study setting: We are planning a preference-based comparative effectiveness clinical trial. We 
will assess whether integrative medicine is more effective than a conventional-only approach 
for improvement of QoL in patients with MM. 
Ethics review: The study protocol was reviewed and approved by the Institutional Review 
Board in accordance with the Helsinki Declaration (0054-24-BNZ). 
Study population: Eligible participants will be recruited from the hematological unit at Bnai-
Zion Medical Center in Haifa, Israel. Inclusion criteria: (1) Age over 18, (2) Diagnosis of 
multiple myeloma, (3) Possibility to answer questionnaires once a month in Hebrew, Arabic or 
Russian, (4) Signing an informed consent form. Exclusion criteria include (1) Age under 18 
years, (2) In patients who will receive acupuncture: platelet level below 20x10^9/L, (3) In 
patients who will receive reflexology: deep vein thrombosis in the leg, (4) Hemodynamic 
instability, (5) Psychiatric disorder impairing competence. 
Group assignment: Patients will choose to participate in one of two study groups. Patients 
willing to attend weekly integrative medicine treatments will be recruited to the intervention 
arm. Patients not willing to come regularly to the clinic for integrative medicine treatments will 
be assigned to the control arm and receive conventional therapy only. 
Blinding: Due to the preference assignation, the study will not be blinded. 
Intervention: All patients will receive conventional MM treatment at the hemato-oncology 
department. Patients recruited to the intervention arm will receive, on top of the defined 
conventional treatment, integrative medicine intervention including acupuncture, touch and/or 
mind-body therapies. The type and frequency of these interventions will be defined by the 
integrative team in coordination with the patient, based on evidence-based data, patient’s 
symptoms, and preferences. The intervention will be given once weekly for 6 weeks. Patients 
in the intervention arm and patients in the control arm that are willing to do so will fill 
questionnaires as of study protocol. The investigators will collect socio-demographic and 
medical data from medical charts of patients from both study arms. 

Training and quality control: Complementary medicine practitioners (acupuncturists, touch 
and mind-body therapists), who will administer the intervention have at least 5 years of clinical 
experience in their discipline among patients with oncological or haemato-oncological 
conditions. A Data Safety Monitoring Board constituted of five experts will control the safety, 
and quality of the intervention as well as data collection on a yearly basis. Dropout, withdrawal, 
treatment adherence and uncollected data will be recorded until completion of the study. 
Outcomes: 
The primary outcome will be the effectiveness of integrative medicine on improving QoL of 
MM patients. The QoL will be evaluated by the EORTC QLQ-MY2 (European Organization 
for the Research and Treatment of Cancer Quality of Life for Myeloma patients) score at 1-2 
weeks after end-of-treatment in intervention group and 7-8 weeks after recruitment in control 
group. It comprises 20 questions that address four myeloma-specific Heath-related QoL 
(HRQoL) domains: Disease Symptoms, Side Effects of Treatment, Future Perspective, and 
Body Image. Domain scores are averaged and transformed linearly to a score ranging from 0-
100. A high score for Disease Symptoms and Side Effects of Treatment represents a high level 
of symptomatology or problems, whereas a high score for Future Perspective and Body Image 
represents better outcomes [10]. 
General HRQoL will be evaluated as well as a secondary outcome using the European 
Organization Research for Treatment of cancer core quality of life (EORTC-QLQ-C30) 
questionnaire summary score at 1-2 weeks after end-of-treatment in intervention group and 7-
8 weeks after recruitment in control group. It is calculated from the mean of 13 of the 15 
quality-of-life (QLQ-C30) scales of the questionnaire = (Physical Functioning+ Role 
Functioning+ Social Functioning+ Emotional Functioning+ Cognitive Functioning+ 100-
Fatigue+ 100-Pain+ 100-Nausea_Vomiting+ 100-Dyspnoea+ 100-Sleeping Disturbances+ 
100-Appetite Loss+ 100-Constipation+ 100-Diarrhoea)/13. Scores range from minimum 0 to 
maximum 100; a higher score represents a higher ("better") level of functioning, or a higher 
("worse") level of symptoms [10]. 
The effect of the intervention on different symptoms experienced by MM patients will be 
evaluated as a secondary outcome by the Edmonton Symptom Assessment System (ESAS) at 
1-2 weeks after end-of-treatment in intervention group and 7-8 weeks after recruitment in 
control group. It assesses the severity over time of nine symptoms common among patients 
with cancer and other advanced illness: pain, tiredness, drowsiness, nausea, shortness of breath, 

appetite, depression, anxiety, and wellbeing. A higher score represents a higher ("worse") level 
of symptoms [11]. 
Compliance to conventional MM treatment will be assessed by calculating the Relative dose 
intensity (RDI) which is the ratio of delivered dose intensity (DDI) of myeloma treatment with 
standard dose intensity (SDI) of myeloma treatment = DDI/SDI, during the one year following 
recruitment. 
Economic evaluation will be based on the EuroQol-5 Dimension (EQ-5D) questionnaire at 1-
2 weeks after end-of-treatment in intervention group and 7-8 weeks after recruitment in control 
group. This questionnaire has been chosen since it is easy to use, validated, translated into 
Hebrew, Russian and Arabic, not disease-specific and permits calculation of utility scores and 
quality-adjusted life years (QALY) allowing economic analysis [12].  
Finally, the impact of the intervention on MM treatment outcomes (overall response rate, 
progression-free survival and overall survival) will be evaluated once in 3 months from 
screening and until 2 years post recruitment and compared between study groups. 
Safety and adverse events: A checklist with acupuncture adverse events based on the AcupAE 
questionnaire [13] will be used to evaluate acupuncture-associated safety events after each 
treatment. For non-acupuncture complementary medicine therapies, the practitioner will 
directly question and evaluate the patient after each intervention for possible safety events. 
Specific integrative medicine interventions may be stopped if significant side effects are of 
concern. Severe adverse events requiring treatment cessation will include anaphylactic shock, 
pneumothorax, massive bleeding or infection in the acupoint area requiring systemic antibiotic 
treatment. 
Criteria for discontinuation: Participants may be discontinued from the study if they voluntary 
withdraw informed consent, for safety reasons or due to significant non-compliance with the 
study protocol as judged by the Principal Investigator. Reasons for discontinuation will be 
recorded and patients withdrawn from the study will be included in the intention-to-treat 
analysis. 
Sample size calculation: Since no previous study has evaluated similar data, we aimed to 
obtain a medium effect size (Cohen’s d 0.6). Considering a Type I error (alpha) of 0.05, a 
power of 0.80, and a two-tails comparison of means between the two study groups using 

G*Power 3.1.9.4 software, we estimated that to achieve a Cohen’s d of 0.6, a minimum of 90 
patients (45 patients in each group) was required. 
Statistical methods: Data analysis will be performed using IBM SPSS Statistics software. 
Demographic and clinical data will be analyzed at baseline to measure the balance among the 
study groups. Quantitative variables will be described using mean and standard deviation or 
median with range (minimum and maximum) depending on their distribution. Qualitative 
variables will be described using frequency and percentage distributions. For comparing 
normally distributed variables between our study groups, we will use the t-test for independent 
samples. For comparing variables that do not distribute normally between our study groups, 
we will use the Mann-Whitney test. For comparing qualitative variables between our study 
groups, we will use the independent Chi-square test and Fisher exact test. Survival analyses 
will be performed using the Kaplan-Meier product limit survival estimator with log-rank 
between-group comparison, and Cox regression will be performed for multivariate adjustment 
of potential confounders. Hazard ratio (HR) with confidence intervals (CI) will be calculated 
for each independent variable and controlled for all other independent variables in the 
regression. All comparisons will be two-sided with significance level set at p<0.05. 

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