The 1,087 patients with MM who met study inclusion criteria included 292 of normal weight, 472 overweight, 198 obese, and 125 severely obese. Median follow-up of survivors is 63 (range 1-144) months, 61 (3-144) months, 60 (3-133) months and 59 (3-131) months for the respective BMI categories.
Baseline patient characteristics are shown in . Obese patients were younger than their non-obese counterparts. There was a higher prevalence of diabetes among obese patients. Obese transplant recipients also had less frequent hypercalcemia, severe anemia, and renal insufficiency. A higher proportion of severely obese patients were in complete or partial response at time of transplant.
Outcomes after Autologous Transplantation:
In the study population as a whole, there was no clear effect of BMI on PFS, OS, progression or NRM. We identified a statistically significant interaction between BMI and conditioning regimen for PFS and progression. Among those receiving melphalan alone, there was no clear association between BMI and these outcomes, with PFS at 5 years of 17% of normal weight patients, 18% of overweight patients, 21% of obese patients, and 14% of severely obese patients (p=0.65). Among those receiving melphalan and TBI, obese and severely obese patients had superior PFS and OS than did normal and overweight patients, with PFS at 5 years of 23% in normal weight patients, 17% in overweight patients, 43% in obese patients, and 55% in severely obese patients (p=0.005). P-values for the interactions between BMI and conditioning regimen were highly significant for PFS (p=0.0063) and progression (p=0.0085), with borderline significance for OS (p=0.012), but not significant for NRM (p=0.43). The effect of BMI on outcomes after transplant was therefore restricted to patients receiving melphalan with TBI, with obese patients having better outcomes, mediated primarily through a lower risk of disease progression.
To exclude confounding by baseline imbalances, we constructed multivariable models of PFS, OS, and progression using all potential confounders. These models included each variable individually, in groups of related variables, and in a single model using all variables, none of which showed any evidence of confounding, with no change in the estimate of effect of BMI on outcomes for patients receiving melphalan alone or melphalan with TBI (data not shown). Final multivariable models, constructed using a forward/backward stepwise algorithm, confirmed the effects of BMI on PFS, progression and OS, as shown in Tables , , and . A multivariate model for NRM (not shown), showed no evidence of confounding, and BMI did not have any clear effect on this outcome. Estimated probabilities of all these outcomes based on the final multivariate models are shown in .
Multivariate analysis of progression-free survival
Multivariate analysis of progression of MM
Multivariate analysis of overall survival
Figure 1 Estimated probabilities of time-to-event outcomes based on final multivariate models. Overall and progression-free survival, time to progression, and time to treatment-related mortality are shown for each BMI category for the entire cohort (1st column) (more ...)
Effects of Melphalan Dose and Dose Reduction
Doses of melphalan were compared among BMI groups as absolute doses and as doses per m2 of BSA calculated using ABW, IBW, and adjusted IBW. As expected with BSA-based dosing, patients who were more obese received higher absolute doses of melphalan, both when melphalan was given alone and when it was given in combination with TBI (). With both conditioning regimens, patients who were more obese received a lower dose per m2
of actual BSA (i.e. using ABW to calculate BSA). Using IBW or adjusted IBW to calculate BSA resulted in normalized doses that were closer among BMI groups, though there were still significant differences among the groups. When compared on the basis of melphalan dose per kg of body weight,(33
) more obese patients received a lower dose of melphalan per kg of ABW.
Melphalan dosing by Body Mass Index.
We further investigated the effect of chemotherapy dosing decisions in obese patients. A full dose of melphalan was defined as 200 mg/m2 (calculated by ABW) for conditioning regimens using melphalan alone and as 140 mg/m2 for transplants using melphalan with TBI. A reduced dose of melphalan was defined as <90% of the full dose. Using this definition, reduced doses of melphalan were given to 78% of severely obese, 56% of obese, 32% of overweight, and 11% of normal weight patients (p<0.0001). Therefore, the odds of dose reduction were 30 (95% confidence interval 17-53) times higher for severely obese patients, 11 (95%CI 7-17) times higher for obese patients, and 4 (95%CI 3-6) times higher for overweight patients, compared with normal weight patients. Dose reduction was also more common for patients with renal insufficiency (odds ratio 2.0, 95%CI 1.2-3.4), history of hypertension (OR 1.7, 95%CI 1.2-2.4) or diabetes (OR 1.8, 95%CI 1.2-2.7), non-Caucasian race (OR 1.4, 95%CI 1.1-2.0), or transplant in the period from 2001-2003 (OR 1.4 compared to transplant in 1995-2000, 95%CI 1.1-1.8). Dose reduction was not associated with other variables, including age, performance status, number of prior therapies, or disease status at time of transplant.
There was no evidence of an effect of melphalan dose reduction on PFS. Receipt of a reduced dose of melphalan was associated with a univariate hazard ratio for PFS of 1.07 (95%CI 0.92-1.23), and in a multivariate analysis (controlling for renal function, performance status, age, race, gender, history of hypertension or diabetes, disease status, and year of transplant) the hazard ratio associated with melphalan dose reduction was 0.88 (95% CI 0.70-1.10). We also found no effect of melphalan dose on PFS, regardless of whether the dose was specified as total melphalan administered, as the dose per m2 of body surface area (with, in successive analyses, the BSA calculated using ABW, adjusted IBW, or IBW), or as the dose per kg of ABW. For the absolute dose of melphalan, the hazard ratio associated with a 10 mg increase in dose was 0.99 (95%CI 0.98-1.01); the hazard ratios per 10 mg/m2 increase in dose were 1.00 (95%CI 0.97-1.04), 0.99 (95%CI 0.96-1.02), and 1.01 (95%CI 0.99-1.04) when BSA was calculated with actual, adjusted ideal, and IBW, respectively; and the hazard ratio per 1 mg/kg increase in dose was 1.05 (95%CI 0.95-1.16) when the dose was calculated per kg of ABW. Repeating these analyses in the population of obese and severely obese patients yielded similar results (data not shown). Therefore, none of these analyses showed any effect of variation in chemotherapy dose on PFS.
Dose of TBI
We further investigated the reason for the restriction of the effect of obesity to TBI-containing transplants. Most patients received a planned dose of 12 Gy (65% of normal and overweight, 74% of obese, and 68% of severely obese patients), with a few patients receiving 13 Gy (9% of normal and 10% of overweight, none of the obese or severely obese), 10-11 Gy (12% of normal, 13% of overweight, 16% of obese, and 23% of severely obese), or <10 Gy; these differences were not significant (overall p-value 0.75). There was no discernible effect of TBI dose on PFS and no evidence that the TBI dose confounded the effect of obesity on PFS (data not shown).